Short-acting benzodiazepines

ABSTRACT

It has now been found that compounds of the present invention as described in Benzodiazepine derivatives of Formula (I) containing a carboxylic ester moiety and thereby capable of being inactivated by nonspecific tissue esterases in an organ-independent elimination mechanism and thereby providing a more predictable and reproducible pharmacodynamic profile. The compounds of the present invention are suitable for therapeutic purposes, including sedative-hypnotic, anxiolytic, muscle relaxant and anticonvulsant purposes and are useful to be administered intravenously in the following clinical settings: preoperative sedation, anxiolysis, and amnestic use for perioperative events; conscious sedation during short diagnostic, operative or endoscopic procedures; as a component for the induction and maintenance of general anesthesia, prior and/or concomitant to the administration of other anesthetic agents; ICU sedation.

FIELD OF THE INVENTION

The present invention relates to benzodiazepine derivatives, topharmaceutical compositions containing them and to their use inmedicine. More particularly, the present invention relates tobenzodiazepine derivatives suitable for therapeutic purposes, includingsedative-hypnotic, anxiolytic, muscle relaxant and anticonvulsantpurposes.

BACKGROUND OF THE INVENTION

The broad neuropharmacology elicited from the benzodiazepine class ofcompounds is generally attributed to their binding to a site on aspecific receptor/chloride ion channel complex known as the GABA_(A)receptor. Benzodiazepine-receptor binding potentiates the binding of theinhibitory neurotrarsmitter γ-aminobutyric acid (GABA) to the complex,thereby leading to inhibition of normal neuronal function. In additionto the therapeutic purposes listed above, benzodiazepines have been usedwidely for anesthesia, particularly as a premedication or as a componentin the induction and/or maintenance of anesthesia. See generally,Goodman and Gilman's The Pharmacological Basis of Therapeutics, EighthEdition; Gilman, A. G.; Rall, T. W.; Nies, A. S.; Taylor, P., Eds.;Pergamon Press: New York, 1990; pp. 303-304, 346-358.

Shorter-acting benzodiazepines that may provide faster recovery profileshave been the subject of recent clinical investigations (W. Hering etal., Anesthesiology 1996, 189, 85 (Suppl.); J. Dingemanse et al., Br. J.Anaesth 1997, 79, 567-574.) Recent patent filings also describebenzodiazepines of interest. (WO 96/23790; WO 96/20941; U.S. Pat. No.5,665,718). Other publications that describe benzodiazepinones includeE. Manghisi and A. Salimbemi, Boll. Chim. Farm. 1974, 113, 642-644), W.A. Khan and P. Singl, Org. Prep. Proc. Int. 1978, 10, 105-111 and J. B.Hester, Jr, et al. J. Med. Chem. 1980, 23, 643-647. Benzodiazepines inpresent practice, such as diazepam, lorazepam, and midazolam all undergometabolism by hepatic-dependent processes. Active metabolites, which areoften much more slowly metabolized than the parent drug, can begenerated by these hepatic mechanisms in effect prolonging the durationof action of many benzodiazepines (T. M. Bauer et al., Lancet 1995, 346,145-7). Inadvertent oversedation has been associated with the use ofbenzodiazepines (A. Shafer, Crit Care Med 1998, 26, 947-956),particularly in the ICU, where benzodiazepines, such as midazolam, enjoyfrequent use. However, the benzodiazepine compounds of this inventiondiffer from benzodiazepines in present-day clinical practice.

SUMMARY OF THE INVENTION

It has now been found that compounds of the present invention asdescribed in Formula (I) possess certain advantages because of theirstructural design. The benzodiazepines described by this invention allcontain a carboxylic ester moiety and are inactivated by nonspecifictissue esterases. An organ-independent elimination mechanism ispredicted to be characteristic of the benzodiazepines of this invention,providing a more predictable and reproducible pharmacodynamic profile.

The compounds of the present invention are suitable for therapeuticpurposes, including sedative-hypnotic, anxiolytic, muscle relaxant andanticonvulsant purposes. The compounds of the present invention areshort-acting CNS depressants that are useful to be administeredintravenously in the following clinical settings: preoperative sedation,anxiolysis, and amnestic use for perioperative events; conscioussedation during short diagnostic, operative or endoscopic procedures; asa component for the induction and maintenance of general anesthesia,prior and/or concomitant to the administration of other anestheticagents; ICU sedation.

DETAILED DESCRIPTION OF THE INVENTION

Thus it is provided according to a first aspect of the present inventioncompounds of Formula (I):

whereinW is H, C₁-C₄ branched alkyl, or a straight chained alkyl;X is CH₂, NH, or NCH₃; n is 1 or 2;Y is O or CH₂; m is 0 or 1, provided that if X is CH₂, n is 1 and m is0, then R¹ is not CH₂CH₃;Z is O; p is 0 or 1;R¹ is H, a C₁-C₇ straight chain alkyl, a C₃-C₇ branched chain alkyl, aC₁-C₄haloalkyl, a C₃-C₇ cycloalkyl, an aryl, a heteroaryl, an aralkyl,or a heteroaralkyl;R² is phenyl, 2-halophenyl, or 2-pyridyl,R³ is H, Cl, Br, F, I, CF₃, or NO₂;(1) R⁴ is H, C₁-C₄ alkyl, or dialkylaminoalkyl and R⁵ and R⁶ togetherrepresent a single oxygen or S atom which is linked to the diazepinering by a double bond and p is zero or 1 (as depicted in formula Ia); or(2) R⁴ and R⁵ together form a double bond in the diazepine ring and R⁶represents the group NHR⁷ wherein R⁷ is H, C₁₋₄ alkyl, C₁₋₄hydroxyalkyl, benzyl or benzyl mono or disubstituted independently withhalogen substituents, C₁₋₄alkylpyridyl or C₁₋₄ alkylimidazolyl and p iszero (as depicted in formula Ib); or (3) R⁴, and R⁶ form the group—CR⁸═U—V═ wherein R⁸ is hydrogen, C₁₋₄ alkyl or C₁₋₃ hydroxyalkyl, U isN or CR⁹ wherein R⁹ is H, C₁₋₄alkyl, C₁₋₃ hydroxyalkyl orC₁₋₄alkoxy-C₁₋₄alkyl, V is N or CH and p is zero (as depicted in formulaIc);or pharmaceutically acceptable salts and or solvates thereof.

The term “aryl,” alone or in combination, is defined herein as amonocyclic or polycyclic group, preferably a monocyclic or bicyclicgroup, e.g., phenyl or naphthyl, which can be unsubstituted orsubstituted, for example, with one or more and, in particular, one tothree substituents selected from halogen, C₁-C₄ branched or straightchained alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, hydroxy, nitro, amino, andthe like. The term “heteroaryl” is defined herein as a 5-membered or6-membered heterocyclic aromatic group which can optionally carry afused benzene ring and wherein said 5-membered or 6-memberedheterocyclic aromatic group can be unsubstituted or substituted, forexample, with one or more and, in particular, one to three substituentsselected from halogen, C₁-C₄ branched or straight chained alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, hydroxy, nitro, amino, and the like. The term“alkoxy,” alone or in combination, is defined herein to include an alkylgroup, as defined earlier, which is attached through an oxygen atom tothe parent molecular subunit. Exemplary alkoxy groups include but arenot necessarily limited to methoxy, ethoxy and isopropoxy. The term“aralkyl” is defined herein as an alkyl group, as defined earlier, inwhich one of the hydrogen atoms is replaced by an aryl group. The term“heteroaralkyl” is defined herein as an alkyl group, as defined earlier,in which one of the hydrogen atoms is replaced by a heteroaryl group.

Exemplary branched or straight chained C₁-C₄ alkyl groups include butare not necessarily limited to methyl, ethyl, propyl, isopropyl,isobutyl and n-butyl. Exemplary C₁-C₇ straight chain alkyl groupsinclude, but are not necessarily limited to, methyl, ethyl, propyl,n-butyl, n-hexyl and n-heptyl. Exemplary C₃-C₇ branched chain alkylgroups include, but are not necessarily limited to, isopropyl, isobutyl,sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl and isohexyl.Exemplary C₃-C₇ cycloalkyl groups include, but are not necessarilylimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl. Exemplary C₁-C₄ haloalkyl groups include, but are notnecessarily limited, to methyl, ethyl, propyl, isopropyl, isobutyl andn-butyl substituted independently with one or more halogens, e.g.,fluoro, chloro, bromo and iodo.

The compounds of formula (I) wherein R⁵ and R⁶ together represent anoxygen or sulphur atom linked to the diazepine ring via a double bondrepresent a first embodiment of a first aspect of the present inventionand are conveniently represented by the formula (1a):

wherein R¹, R², R³, W, X, Y, Z, p, n and m have the meanings defined informula (I).

In one embodiment of the compounds of formula (1a) there are providedcompounds wherein

W is H;

X is CH₂ or NH; n is 1;

Y is CH₂; m is 0 or 1, provided that if X is CH₂, n is 1 and m is 0,then R¹ is not CH₂CH₃;

Z is O; p is 0 or 1;

R¹ is H, CH₃, CH₂CH₃, (CH₂)₂CH₃, (CH₂)₃CH₃, CH₂(CH₃)₂, CH₂CH(CH₃)₂,C(CH₃)₃, benzyl, 4-pyridylmethyl or 3-pyridylmethyl;

R² is phenyl, 2-fluorophenyl, 2-chlorophenyl or 2-pyridyl;

R³ is Cl, Br or NO₂;

R⁴ is H, CH₃ or CH₂CH₂N(CH₂CH₃)₂;

R⁵ and R⁶ together are O or S; or pharmaceutically acceptable salts andsolvates thereof.

A further embodiment of the compounds of formula (Ia) is that wherein:

W is H;

X is CH₂ or NH; n is 1;

Y is CH₂; m is 1;

p is 0;

R¹ is H, CH₃, CH₂CH₃. (CH₂)₂CH₃, (CH₂)₃CH₃, CH₂(CH₃)₂, CH₂CH(CH₃)₂,C(CH₃)₃, benzyl, 4-pyridylmethyl or 3-pyridylmethyl; provided that if R¹is 3-pyridylmethyl or 4-pyridylmethyl, then X is CH₂, n is 1, Y is CH₂,m is 0 or 1, R² is 2-fluorophenyl, R³ is Cl, R⁴ is H and R⁵ and R⁶together is oxygen;

R² is phenyl, 2-fluorophenyl, 2-chlorophenyl or 2-pyridyl, R³ is Cl, Bror NO₂;

R⁴ is H, CH₃ or CH₂CH₂N(CH₂CH₃)₂; provided that when R⁴CH₂CH₂N(CH₂CH₃)₂, then X is CH₂, n is 1, Y is CH₂, m is 1, R¹ is CH₃ orbenzyl, R² is 2-fluorophenyl, R³ is Cl and R⁵ and R⁶ together representO;

R⁵ and R⁶ together are O or S; or pharmaceutically acceptable salts andsolvates thereof.

In yet a further embodiment of the present invention are the compoundsof formula (1a) wherein

W is H;

X is CH₂ or NH; n is 1;

Y is CH₂; m is 0 or 1, provided that if X is CH₂ and m is 0, then R¹ isnot CH₂CH₃;

p is 0;

R¹ is CH₃, CH₂CH₃, (CH₂)₂CH₃,(CH₂)₃CH₃, CH₂(CH₃)₂, CH₂CH(CH₃)₂, C(CH₃)₃,benzyl or 4-pyridylmethyl;

R² is 2-fluorophenyl, 2-chlorophenyl or 2-pyridyl,

R³ is Cl, Br or NO₂;

R⁴ is H, CH₃ or CH₂CH₂N(CH₂CH₃)₂;

R⁵ and R⁶ together are O or S; or

pharmaceutically acceptable salts and solvates thereof.

Yet another embodiment of the present invention are compounds of formula(Ia) wherein

W is H;

X is CH₂ or NH; n is 1;

Y is CH₂; m is 0 or 1, provided that if X is CH₂ and m is 0, then R¹ isnot CH₂CH₃;

p is 0;

R¹ is CH₃, CH₂CH₃, (CH₂)₂CH₃, (CH₂)₃CH₃, CH₂(CH₃)₂, CH₂CH(CH₃)₂,C(CH₃)₃, benzyl or 4-pyridylmethyl; provided that when R¹ is4-pyridylmethyl, then X is CH₂,

Y is CH₂, m is 1, R² is 2-fluorophenyl, R³ is Cl, R⁴ is H and R⁵ and R⁶together represent oxygen;

R² is 2-fluorophenyl, 2-chlorophenyl or 2-pyridyl,

R³ is Cl, Br or NO₂;

R⁴ is H, CH₃ or CH₂CH₂N(CH₂CH₃)₂; provided that when R⁴ isCH₂CH₂N(CH₂CH₃)₂, then X is CH₂, Y is CH₂, m is 1, R¹ is CH₃ or benzyl,R² is 2-fluorophenyl, R³ is Cl and R⁵ and R⁶ together represent O;

R⁵ and R¹ together represent O or S; or pharmaceutically acceptablesalts and solvates thereof.

Yet another embodiment of the first aspect of the invention arecompounds of formula (Ia) or pharmaceutically acceptable salts andsolvates thereof wherein in each compound W is H and wherein X, n, Y, m,Z, p and R¹⁻⁶ for each compound are as follows: X n Y m Z p R¹ R² R³ R⁴R⁵and R⁶ CH₂ 1 CH₂ 1 — 0 CH₃ 2-fluorophonyl Cl H O CH₂ 1 — 0 — 0 CH₃2-fluorophenyl Cl H O CH₂ 1 CH₂ 1 — 0 CH₃ 2-fluorophenyl Br H O CH₂ 1CH₂ 1 — 0 benzyl 2-fluorophenyl Cl H O CH₂ 1 — 0 — 0 benzyl2-fluorophenyl Cl H O CH₂ 1 CH₂ 1 — 0 CH₃ 2-chlorophenyl Cl H O CH₂ 1CH₂ 2 — 0 CH₃ 2-fluorophenyl Cl H O CH₂ 1 CH₂ 1 — 0 benzyl 2-pyridyl ClH O CH₂ 1 CH₂ 1 — 0 CH₃ 2-pyridyl Br H O CH₂ 1 CH₂ 1 — 0 CH₃ 2-pyridylCl H O CH₂ 1 CH₂ 2 — 0 C(CH₃)₃ 2-fluorophenyl Cl H O CH₂ 1 CH₂ 1 — 0 CH₃2-fluorophenyl NO₂ H O CH₂ 1 CH₂ 1 — 0 (CH₂)₂CH₃ 2-pyridyl Cl H O CH₂ 1CH₂ 1 — 0 CH₂CH₃ 2-pyridyl Cl H O CH₂ 1 CH₂ 1 — 0 4-pyridyl-methyl2-fluorophenyl Cl H O CH₂ 1 CH₂ 1 — 0 (CH₂)₃CH₃ 2-fluorophenyl Cl H OCH₂ 1 CH₂ 1 — 0 (CH₂)₃CH₃ 2-pyridyl Cl H O CH₂ 1 CH₂ 1 — 0 CH₂CH(CH₃)₂2-pyridyl Cl H O CH₂ 1 — 0 — 0 CH₂CH₃ 2-fluorophenyl Cl H O CH₂ 1 CH₂ 1— 0 CH(CH₃)₂ 2-fluorophenyl Cl H O CH₂ 1 CH₂ 1 — 0 CH₃ 2-fluorophenyl ClCH₂CH₂N—(CH₂CH₃)₂ O CH₂ 1 CH2 1 — 0 CH₃ 2-fluorophenyl Cl CH₃ O CH₂ 1 —0 — 0 benzyl 2-fluorophenyl Cl CH₃ O CH₂ 1 CH₂ 1 — 0 benzyl2-fluorophenyl Cl CH₂CH₂N—(CH₂CH₃)₂ O NH 1 CH₂ 1 — 0 CH₃ 2-chlorophenylCl H O NH 1 CH₂ 2 — 0 CH₃ 2-chlorophenyl Cl H O CH₂ 1 CH₂ 1 — 0 CH₃2-fluorophenyl Cl H S CH₂ 1 CH₂ 1 — 0 CH₃ 2-chlorophenyl Cl H S CH₂ 1CH₂ 1 — 0 CH₃ 2-pyridyl Cl H S CH₂ 1 CH₂ 1 O 1 CH₃ 2-fluorophenyl Cl H OCH₂ 1 CH₂ 1 — 0 benzyl phenyl NO₂ H O CH₂ 1 CH₂ 1 — 0 CH₃ 2-fluorophenylH H O CH₂ 1 CH₂ 1 — 0 CH₃ 2-pyridyl NO₂ H O CH₂ 1 CH₂ 1 — 0 benzyl2-pyridyl NO₂ H O CH₂ 1 CH₂ 1 — 0 benzyl 2-fluorophenyl H H O CH₂ 1 CH₂1 — 0 CH₃ phenyl NO₂ H O NH 1 CH₂ 2 — 0 (CH₂)₃CH₃ 2-fluorophenyl Cl H OCH₂ 1 — 0 — 0 3-pyridyl-methyl 2-fluorophenyl Cl H O CH₂ 1 — 0 — 04-pyridyl-methyl 2-fluorophenyl Cl H O

Yet another embodiment of the first aspect of the invention arecompounds of formula (Ia) or pharmaceutically acceptable salts andsolvates thereof wherein in each compound W is H and wherein X, n, Y, m,Z, p and R¹⁻⁶ for each compound are as follows: X n Y m Z p R¹ R² R³ R⁴R⁵ and R⁶ CH₂ 1 CH₂ 1 — 0 CH₃ 2-fluorophenyl Cl H O CH₂ 1 — 0 — 0 CH₃2-fluorophenyl Cl H O CH₂ 1 CH₂ 1 — 0 CH₃ 2-fluorophenyl Br H O CH₂ 1CH₂ 1 — 0 benzyl 2-fluorophenyl Cl H O CH₂ 1 — 0 — 0 benzyl2-fluorophenyl Cl H O CH₂ 1 CH₂ 1 — 0 CH₃ 2-chlorophenyl Cl H O CH₂ 1CH₂ 2 — 0 CH₃ 2-fluorophenyl Cl H O CH₂ 1 CH₂ 1 — 0 benzyl 2-pyridyl ClH O CH₂ 1 CH₂ 1 — 0 CH₃ 2-pyridyl Br H O CH₂ 1 CH₂ 1 — 0 CH₃ 2-pyridylCl H O CH₂ 1 CH₂ 2 — 0 C(CH₃)₃ 2-fluorophenyl Cl H O CH₂ 1 CH₂ 1 — 0 CH₃2-fluorophenyl NO₂ H O CH₂ 1 CH₂ 1 — 0 (CH₂)₂CH₃ 2-pyridyl Cl H O CH₂ 1CH₂ 1 — 0 CH₂CH₃ 2-pyridyl Cl H O CH₂ 1 CH₂ 1 — 0 4-pyridylmethyl2-fluorophenyl Cl H O CH₂ 1 CH₂ 1 — 0 (CH₂)₃CH₃ 2-fluorophenyl Cl H OCH₂ 1 CH₂ 1 — 0 (CH₂)₃CH₃ 2-pyridyl Cl H O CH₂ 1 CH₂ 1 — 0 CH₂CH(CH₃)₂2-pyridyl Cl H O CH₂ 1 — 0 — 0 CH₂CH₃ 2-fluorophenyl Cl H O CH₂ 1 CH₂ 1— 0 CH(CH₃)₂ 2-fluorophenyl Cl H O CH₂ 1 CH₂ 1 — 0 CH₃ 2-fluorophenyl ClCH₂CH₂N(CH₂CH₃)₂ O CH₂ 1 CH₂ 1 — 0 CH₃ 2-fluorophenyl Cl CH₃ O CH₂ 1 — 0— 0 benzyl 2-fluorophenyl Cl CH₃ O CH₂ 1 CH₂ 1 — 0 benzyl 2-fluorophenylCl CH₂CH₂N(CH₂CH₃)₂ O NH 1 CH₂ 1 — 0 CH₃ 2-chlorophenyl Cl H O NH 1 CH₂2 — 0 CH₃ 2-chlorophenyl Cl H O CH₂ 1 CH₂ 1 — 0 CH₃ 2-fluorophenyl Cl HS CH₂ 1 CH₂ 1 — 0 CH₃ 2-chlorophenyl Cl H S CH₂ 1 CH₂ 1 — 0 CH₃2-pyridyl Cl H S CH₂ 1 CH₂ 1 O 1 CH₃ 2-fluorophenyl Cl H O

Yet another embodiment of the first aspect of the invention arecompounds of formula (Ia) or pharmaceutically acceptable salts andsolvates thereof wherein in each compound W is H, and p is 0, andwherein X, n, Y, m, R¹⁻⁶ for each compound are as follows: X n Y m R¹ R²R³ R⁴ R⁵ and R⁶ CH₂ 1 CH₂ 1 CH₃ 2-fluorophenyl Cl H O CH₂ 1 CH₂ 1 CH₃2-fluorophenyl Br H O CH₂ 1 CH₂ 1 CH₃ 2-pyridyl Cl H O CH₂ 1 CH₂ 1 CH₃2-fluorophenyl Cl CH₃ O

Yet another embodiment of the first aspect of the invention is acompound of formula (Ia) or a pharmaceutically acceptable salt andsolvate thereof wherein W is H, X is CH₂, n is 1, Y is CH₂, m is 1, p is0, R¹ is CH₃, R² is 2-fluorophenyl, R³ is Cl, R⁴ is H and R⁵ and R⁶together represent oxygen.

The compounds of formula (I) wherein R⁴ and R⁵ together form a doublebond in the diazepine ring and wherein R⁶ is the group NHR⁷ represent afurther embodiment of the first aspect of the invention and areconveniently represented by formula (1b).

wherein R¹, R², R⁴, R⁷, W, X, Y, n and m have the meanings defined informula (I).

In a further embodiment of the first aspect of the invention arecompounds of formula (Ib) or pharmaceutically acceptable salts andsolvates thereof wherein W is H, X is CH₂, n is 1, Y is CH₂, m is 1, R¹is CH₃, R² is 2-fluorophenyl, 2-chlorophenyl or 2-pyridyl, R³ is Cl orBr and R⁷ is CH₃. CH₂CH₃, benzyl, 4-pyridylmethyl-, 4-pyridylethyl,CH(CH₃)₂, 4-imidazolylethyl or CH₂CH₂OH.

In yet another embodiment of the first aspect of the invention arecompounds of formula (Ib) or pharmaceutically acceptable salts andsolvates thereof wherein in each compound W is H, X is CH₂, n is 1, Y isCH₂, m is 1, R¹ is CH₃, and wherein R², R³ and R⁷ for each compound areas follows: R² R³ R⁷ 2-fluorophenyl Cl CH₃ 2-pyridyl Cl CH₃2-fluorophenyl Cl CH₂CH₃ 2-fluorophenyl Cl benzyl 2-fluorophenyl Cl4-pyridylmethyl 2-fluorophenyl Cl 4-pyridylethyl 2-fluorophenyl ClCH₂CH(CH₃)₂ 2-fluorophenyl Cl 2-(4-imidazolyl)ethyl 2-fluorophenyl ClCH₂CH₂OH 2-fluorophenyl Br CH₃ 2-chlorophenyl Cl CH₃

Yet another embodiment of the first aspect of the invention arecompounds of formula (Ib) or pharmaceutically acceptable salts andsolvates thereof wherein in each compound W is H, X is CH₂, n is 1, Y isCH₂, m is 1, R¹ is CH₃, R² is 2-fluorophenyl, R³ is chlorine or bromineand R⁷ is methyl.

Yet another embodiment of the first aspect of the invention is acompound of formula (Ib) or a pharmaceutically acceptable salt andsolvate thereof wherein W is H, X is CH₂, n is 1, Y is CH₂, m is 1, R¹is CH₃, R² is 2-fluorophenyl, R³ is Cl and R⁴ is CH₃.

The compounds of formula (I) where the groups R⁴ and R⁵ and R⁶ togetherform the group —CR⁸═U—V=represent a further embodiment of the firstaspect of the invention and may be conveniently represented by thecompound of formula (1c):

wherein R¹, R², R⁸, U, V, W, X, Y, n and m have the meanings given informula (I).

In yet another embodiment of the first aspect of the invention arecompounds of formula (Ic) or pharmaceutically acceptable salts andsolvates thereof wherein

W is H,

X is CH₂, n is 1;

Y is CH₂, m is 1;

R¹ is CH₃ or CH₂CH(CH₃)₂;

R¹ is 2-fluorophenyl, 2-chlorophenyl or 2-pyridyl;

R¹ is Cl or Br;

R⁸ is H, CH₃ or CH₂OH;

R⁹ is H, CH₃, CH₂OH or CH₂O-t-butyl;

U is CR⁹ or N; and

V is N or CH.

Yet another embodiment of the first aspect of the invention arecompounds of formula (Ic) or pharmaceutically acceptable salts andsolvates thereof wherein

W is H,

X is CH₂, n is 1;

Y is CH₂, m is 1;

R¹ is CH₃ or CH₂CH(CH₃)₂; provided that when R¹ is CH₂CH(CH₃)₂, then R²is 2-fluorophenyl, R³ is Cl, R⁸ is CH₃, U is N and V is N;

R² is 2-fluorophenyl, 2-chlorophenyl or 2-pyridyl;

R³ is Cl or Br;

R⁸ is H, CH₃ or CH₂OH;

R⁹ is H, CH₃, CH₂OH or CH₂O-t-butyl;

U is CR⁹ or N; and

V is N or CH.

Yet another embodiment of the first aspect of the invention arecompounds of formula (Ic) or pharmaceutically acceptable salts andsolvates thereof wherein in each compound W is H, X is CH₂, n is 1, Y isCH₂, m is 1 and wherein R¹, R², R³, R⁸, U and V for each compound are asfollows: R¹ R² R³ R⁸ U V CH₃ 2-fluorophenyl Cl H CH N CH₃ 2-fluorophenylCl CH₃ CH N CH₃ 2-fluorophenyl Cl H C—CH₃ N CH₃ 2-fluorophenyl Cl HC—CH₂OH N CH₃ 2-fluorophenyl Cl CH₂OH CH N CH₃ 2-pyridyl Cl H CH N CH₃2-pyridyl Cl CH₃ CH N CH₃ 2-pyridyl Br CH₃ CH N CH₃ 2-pyridyl Br H C—CH₃N CH₃ 2-pyridyl Cl H C—CH₃ N CH₃ 2-pyridyl Cl H C—CH₂OH N CH₃ 2-pyridylCl CH₂OH CH N CH₃ 2-pyridyl Cl CH₃ C—CH₃ N CH₃ 2-chlorophenyl Cl CH₃ N NCH₃ 2-fluorophenyl Cl CH₃ N N CH₂CH(CH₃)₂ 2-fluorophenyl Cl CH₃ N N CH₃2-fluorophenyl Cl H N CH CH₃ 2-fluorophenyl Cl CH₃ N CH CH₃2-fluorophenyl Cl H C—CH₂O-t-butyl N CH₃ 2-pyridyl Cl CH₃ C—CH₂OH N

Yet another embodiment of the first aspect of the invention arecompounds of formula (1c) or pharmaceutically acceptable salts andsolvates thereof wherein in each compound W is H, X is CH₂, n is 1, Y isCH₂, m is 1 and wherein R¹, R², R³, R³, U and V for each compound are asfollows: R¹ R² R³ R⁸ U V CH₃ 2-pyridyl Br CH₃ CH N CH₃ 2-pyridyl Cl CH₃CH N CH₃ 2-fluorophenyl Cl CH₃ N CH CH₃ 2-pyridyl Br H C—CH₃ N

Yet another embodiment of the first aspect of the invention is acompound of formula (Ic) or a pharmaceutically acceptable salt andsolvate thereof wherein in W is H, X is CH₂, n is 1, Y is CH₂, m is 1,R¹ is CH₃, R² is 2-pyridyl, R³ is Br, R⁸ is CH₃, U is CH and V is N.

Those skilled in the art will recognize that a stereocenter exists incompounds of Formula (I). Accordingly, the present invention includesindividual enantiomers of the compounds of Formula (I) substantiallyfree of the other enantiomer, as well as in racemic or other admixturewith the other enantiomer.

General Procedures

As used herein the symbols and conventions used in these processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Standard single-letteror three-letter abbreviations are generally used to designate amino acidresidues which are assumed to be in the L-configuration unless otherwisenoted. Unless otherwise noted, all starting materials were obtained fromcommercial suppliers and used without further purification.Specifically, the following abbreviations may be used in the examplesand throughout the specification: g (grams); mg (milligrams); L(liters); mL (milliliters); μL (microliters); psi (pounds per squareinch); M (molar); mM (millimolar); i. v. (intravenous); Hz (Hertz); MHz(megahertz); mol (moles); mmol (millimoles); RT (room temperature); min(minutes); h (hours); mp (melting point); TLC (thin layerchromatography); HPLC (high pressure liquid chromatography); Tr(retention time); RP (reverse phase); MeOH (methanol); i-PrOH(isopropanol); TEA (triethylamine); TFA (trifluoroacetic acid); TFAA(trifluoroacetic anhydride); THF (tetrahydrofuran); DMSO(dimethylsulfoxide); EtOAc (ethyl acetate); DME (1,2-dimethoxyethane);DCM (dichloromethane); DCE (dichloroethane); DMF(N,N-dimethylformamide); DMPU (N,N′-dimethylpropyleneurea); (CDI(1,1-carbonyldiimidazole); IBCF (isobutyl chloroformate); HOAc (aceticacid); HOSu (N-hydroxysuccinimide); HOBT (1-hydroxybenzotriazole); mCPBA(meta-chloroperbenzoic acid; EDC (ethylcarbodiimide hydrochloride); BOP(bis(2-oxo-3-oxazolidinyl)phosphinic chloride); BOC(tert-butyloxycarbonyl); FMOC (9-fluorenylmethoxycarbonyl); DCC(dicyclohexylcarbodiimide); CBZ (benzyloxycarbonyl); Ac (acetyl); atm(atmosphere); TBAF (tetra-n-butylammonium fluoride); TMSE(2-(trimethylsilyl)ethyl); TMS (trimethylsilyl); TIPS(triisopropylsilyl); TBS (t-butyldimethylsilyl); DMAP(4-dimethylaminopyridine). All references to ether are to diethyl ether;brine refers to a saturated aqueous solution of NaCl. Unless otherwiseindicated, all temperatures are expressed in ° C. (degrees Centigrade).All reactions conducted under an inert atmosphere at room temperatureunless otherwise noted.

¹H NMR spectra were recorded on a Varian VXR-300, a Varian Unity-300, aVarian Unity-400 instrument, or a General Electric QE-300. Chemicalshifts are expressed in parts per million (ppm, δ units). Couplingconstants are in units of hertz (Hz). Splitting patterns describeapparent multiplicities and are designated as s (singlet), d (doublet),t (triplet), q (quartet), m (multiplet), br (broad).

Low-resolution mass spectra (MS) were recorded on a JOEL JMS-AX505HA,JOEL SX-102, or a SCIEX-APIiii spectrometer; high resolution MS wereobtained using a JOEL SX-102A spectrometer. All mass spectra were takenunder electrospray ionization (ESI), chemical ionization (CI), electronimpact (EI) or by fast atom bombardment (FAB) methods. Infrared (IR)spectra were obtained on a Nicolet 510 FT-IR spectrometer using a 1-mmNaCl cell. Rotations were recorded on a Perkin-Elmer 241 polarimeter.All reactions were monitored by thin-layer chromatography on 0.25 mm E.Merck silica gel plates (60F-254), visualized with UV light, 5%ethanolic phosphomolybdic acid or p-anisaldehyde solution. Flash columnchromatography was performed on silica gel (230-400 mesh, Merck).Optical rotations were obtained using a Perkin Elmer Model 241Polarimeter. Melting points were determined using a Mel-Temp IIapparatus and are uncorrected.

Compounds of general formula (I) may be prepared by methods known in theart of organic synthesis as set forth in part by the following synthesisschemes. In all of the schemes described below, it is well understoodthat protecting groups for sensitive or reactive groups are employedwhere necessary in accordance with general principles of chemistry.Protecting groups are manipulated according to standard methods oforganic synthesis (T. W. Green and P. G. M. Wuts (1991) ProtectingGroups in Organic Synthesis, John Wiley & Sons). These groups areremoved at a convenient stage of the compound synthesis using methodsthat are readily apparent to those skilled in the art. The selection ofprocesses as well as the reaction conditions and order of theirexecution shall be consistent with the preparation of compounds ofFormula I. Those skilled in the art will recognize that a stereocenterexists in compounds of Formula I. Accordingly, the present inventionincludes both possible stereoisomers and includes not only racemiccompounds but the individual enantiomers as well. When a compound isdesired as a single enantiomer, it may be obtained by stereospecificsynthesis or by resolution of the final product or any convenientintermediate. Resolution of the final product, an intermediate, or astarting material may be effected by any suitable method known in theart. See, for example, Stereochemistry of Organic Compounds by E. L.Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).

Compounds of Formula (Ia, wherein X═CH₂, R⁴═H, R⁵ and R⁶═O, p=0) can beprepared according to the synthetic sequence shown in Scheme 1a andfurther detailed in the Examples section (vide infra). An appropriateaminobenzophenone (A) is coupled to a suitably protected (e.g., FMOC)amino acid chloride (B) in a suitable solvent, e.g., chloroform, toprovide amide (C) (J. Org. Chem. 1986, 51, 3732-3734).Carbodiimide-mediated coupling (such as with DCC or EDC) can also beused for this condensation. Base-mediated removal of the amineprotecting group (e.g., triethylamine, DCM) and subsequent cyclization(acetic acid, DCE) provides (D), which are compounds of formula Iawherein R⁵ and R⁶ together represent O for compounds wherein R⁴ is asubstituent other than hydrogen, the anilide nitrogen can be alkylatedby deprotonation with a base such as NaH in a suitable solvent (e.g.DMF), followed by addition of an alkylating agent such R⁴I, therebyproviding the N-alkylated compounds (E), which are also represented byformula (Ia).

N4-oxide derivatives of compounds of Formula (I) (Z=O, p=1) can beprepared from compounds of formula (Ia) wherein p is zero according tothe synthetic sequence shown in Scheme 1b. It is readily apparent to oneskilled in the art that benzodiazepinones represented by structure (E)can be oxidized by treatment with mCPBA or other oxidant in a suitablesolvent (e.g., DCM).

Compounds of Formula Ia wherein X is NH and p=0 may be prepared from theappropriate 3-aminobenzodiazepine F, which can be readily prepared bymethods previously described (R. G. Sherrill et al., J. Org. Chem. 1995,60, 730). The 3-amino-1,4-benzodiazepine thus obtained can bemanipulated according to the sequence set forth in Scheme 2 and furtherdetailed in the Examples section (vide infra). Alkylation of the 3-aminocan be achieved by treatment with a 2-haloacetate (e.g. 2-bromoacetate)or conjugate addition to an appropriate unsaturated ester (e.g. methylacrylate), providing derivatives G.

Compounds of Formula Ia (wherein R⁵R⁶═O) can be converted to theircorresponding wherein R⁵R⁶═S with Lawesson's reagent in toluene or othersuitable solvent (J. Org. Chem. 1964, 29, 231-233).

Compounds of formula Ib may be synthesized as shown in Scheme 3 andfurther detailed in the Examples section (vide infra). Thus reaction ofa compound of formula (Ia) wherein R⁴ is hydrogen, R⁵R⁶═O and p is zero(D) with Lawesson's reagent as described above gives the thiolactam (H).

Condensation of the thiolactam (H) with an amine R⁷NH₂ intetrahydrofuran affords the corresponding compounds of Formula (1b).Alternatively, compounds of Formula (1b) can be prepared by addition ofan amine R⁷NH₂ to the iminophosphate (I) in THF, which is prepared byreaction of compound (D) with an appropriate phosphoryl chloridereagent, preferably the bis-morpholinophosphoryl chloride (Ning et al.,J. Org. Chem. 1976, 41, 2720-2724; Ning et al., J. Org. Chem. 1976, 41,2724-2727).

A method of preparation of compounds of formula (1c; U═CR⁹; V═N), is setforth in Scheme 4 and further detailed in the Examples section (videinfra).

These methods are analogous to those described (WO 96/20941, WO96/23790). Reaction between either the thiolactam (H) or iminophosphate(I) and an appropriate an amino alcohol HOCH(R⁸)—CH(R⁹)NH₂ providesadduct (J). Swern oxidation (i. DMSO, TFAA or (COCl)₂; TEA) of thehydroxyl group provides an intermediate ketone or aldehyde thatundergoes cyclodehydration, spontaneously or under appropriate acidicconditions (e.g. p-toluenesulfonic acid, DMF), to provide compounds offormula (1c; U═CR⁹; V═N).

As set forth in Scheme 5, reaction of (I) (J. Med. Chem. 1993, 36,479-490; J. Med. Chem. 1993, 36, 1001-1006) with the anion of isonitrileester (K) delivers imidazole (L) as the product; subsequent removal ofthe ester functionality by methods set forth in the examples (videinfra) provides compounds of formula 1c; U═N; V═CH).

An alternative method for the preparation of compounds of formula (1c;wherein X is CH₂, n is Z, m=0, U═N; V═CH), is set forth in Scheme 6 andfurther detailed in the Examples section (vide infra). C4-unsubstitutedimidazobenzodiazepine (M) is treated with a strong base (preferablypotassium t-butoxide) and the anion is treated with a suitable Michaelacceptor, such as t-butyl acrylate. The resultant ester adduct (N) istreated with a strong acid (e.g., TFA) to remove the t-butyl group andthe carboxylic acid (O) is esterified to provide compounds of Formula(1c) by base-mediated alkylation with an alkyl halide.

Alternative methods to prepare these compounds have also been described(e.g., J. Org. Chem. 1978, 43, 936-944).

Compounds of formula Ic (U═N; V═N), may be prepared as set forth inScheme 7 and further detailed in the Examples section (vide infra).Thiolactam (H) is converted to its corresponding methylthioimidate (P),which then undergoes condensation and cyclodehydration to provide thedesired triazolobenzodiazepine.

Synthesis of Key Intermediates

The following section describes the preparation of intermediates thatmay be used in the synthesis of compounds of Formula I. There may beexamples wherein the starting material can be prepared according to themethods set forth in the synthesis of an intermediate. It should bereadily apparent to one skilled in the art how these methods can beapplied to include all compounds of Formula I.

The synthesis of the FMOC-Glu(OMe)-OH was carried out as described inInt. J. Peptide Protein Res. 1989, 33, 353.

FMOC-Glu(OMe)-OH (80 g, 0.21 mol) was dissolved in CH₂Cl₂ (523 mL). DMF(1 mL) was added followed by dropwise addition of oxalyl chloride (19mL, 0.22 mol). The solution was stirred at room temperature for 4 h, andconcentrated in vacuo to a volume of ca. 200 mL. To this stirringconcentrate was added hexanes by rapid dropwise addition. The resultingslurry was stirred for 30 min and filtered to provide the required acidchloride as a white solid (83 g, 98%).

To a −40° C. solution of 2.5 M n-butyllithium in hexane (400 mL, 1000mmol, 4 eq) and diethyl ether (1 L) was added 2-bromopyridine (173.93 g,1101 mmol, 4.4 eq) over approximately 30 min. The reaction was stirredfor 1 h at −40° C., and then treated with 5-bromoanthranilic acid (54.14g, 250.6 mmol, 1 eq) in THF (1 L). The reaction was warmed to 0° C. andstirred 2 h at 0° C., then quenched with chlorotrimethylsilane (625 mL,4924 mmol, 20 eq). The reaction was stirred 30 min at ambienttemperature, then cooled to 0° C. and quenched with 3N HCl (625 mL). Theaqueous layer was separated, and the organic layer was extracted oncewith 3N HCl. The combined aqueous layers were neutralized with solidsodium hydroxide pellets, with cooling via ice bath. The resultingmixture was extracted with diethyl ether (3×1 L). The combined etherlayers were dried over sodium sulfate, filtered and concentrated to ablack oil, which was subsequently purified by flash chromatography (1 Lsilica gel, 20-30% ethyl acetate/hexane) to give the required compoundas a brown solid (62 g, 224 mmol, 89.3%).

tert-Butyllithium (43.4 mL of a 1.7 M solution in pentane, 73.8 mmol)was added to a solution of N—BOC-4-chloroaniline (7.00 g, 30.8 mmol) inTHF (154 mL) at −78° C. The reaction mixture was stirred for 15 min thenwarmed to −20° C. and stirred an additional 2 h. The reaction mixturewas cooled to −78° C., treated with 2-pyridinecarboxaldehyde (2.92 mL,30.8 mmol), stirred for 2 h, treated with saturated aqueous NaHCO₃ (ca.50 mL), and warmed to room temperature. The mixture was concentratedunder reduced pressure and the residue was extracted with EtOAc (1×500mL). The organic phase was washed with saturated aqueous NaHCO₃ (1×100mL), H₂O (1×100 mL), saturated aqueous NaCl (1×100 mL), dried (Na₂SO₄),and concentrated under reduced pressure. The residue was dissolved inCHCl₃ (150 mL), treated with activated MnO₂ (58% by weight, 30.0 g, 200mmol), and stirred for 18 h. The reaction mixture was filtered through apad of Celite using additional CHCl₃ (ca. 100 mL) and the filtrate wasconcentrated under reduced pressure. Purification by flashchromatography, elution with 9:1 hexane-EtOAc, gave 6.02 g (59%) of theintermediate BOC-protected aminobenzophenone as a foam.

A solution of the BOC-protected aminobenzophenone described above (5.93g, 17.8 mmol) and HCl (18.0 mL of a 4M solution in 1,4-dioxane, 71.3mmol) in CH₂Cl₂ was stirred for 4 h at room temperature thenconcentrated under reduced pressure. The residue was diluted with EtOAc(ca. 200 mL) and treated with saturated aqueous NaHCO₃ until CO₂evolution ceased. The layers were separated and the organic phase waswashed with saturated aqueous NaHCO₃ (1×50 mL), H₂O (1×50 mL), saturatedaqueous NaCl (1×50 mL), dried (Na₂SO₄), and concentrated under reducedpressure to give 3.83 g (92%) of the title compound as a yellowamorphous solid; ¹H NMR (400 MHz, DMSO-d₆) δ 8.68 (d, J=4.6 Hz, 1H),8.02 (ddd, J=7.8, 7.8, 1.6 Hz, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.59 (m,1H), 7.52 (d, J=2.6 Hz, 1H), 7.42 (br s, 2H), 7.31 (dd, J=9.0, 2.6 Hz,1H), 6.89 (d, J=9.0 Hz, 1H); ESIMS 233 (M+H), 107 (base).

A solution of 2-(2-aminobenzoyl)pyridine (1.29 g, 6.32 mmol, Syn. Comm.1996, 26, 721-727) and trifluroacetic anhydride (1.10 mL, 7.79 mmol) inCHCl₃ (35 mL) was heated at 42° C. for 5 h. The reaction mixture wasconcentrated under reduced pressure and the residue was dissolved inEtOAc (ca. 250 mL), washed with saturated aqueous NaHCO₃ (2×50 mL), H₂O(1×50 mL), brine (1×50 mL), dried (Na₂SO₄) and concentrated underreduced pressure to give 1.91 g (99%) of the trifluoracetanilide.

A mixture of KNO₃ (905 mg, 8.96 mmol) in concentrated H₂SO₄ (12 mL) wasadded to a mixture of amide (1.76 g, 5.97 mmol) in concentrated H₂SO₄(18 mL) maintaining the reaction temperature at ≦16° C. with an icebath. The reaction mixture was allowed to warm to room temperature,stirred 4 h, and poured onto ice (ca. 150 g). The mixture wasneutralized by slow addition of 25% aqueous NaOH (ca. 175 mL)maintaining the temperature at ≦18° C. with an ice bath. The aqueouslayer was extracted with EtOAc (2×200 mL). The combined organic extractswere washed with H₂O (1×100 mL), brine (1×100 mL), dried (Na₂SO₄) andconcentrated under reduced pressure to give a solid. Purification byflash chromatography, elution with 20% EtOAc-hexane, to provide 1.19 g(59%) of the 4-nitro-trifluoracetanilide compound as a yellow solid.

A mixture of the nitro compound prepared as above (1.14 g, 3.36 mmol),MeOH (33 mL), and H₂O (13 mL) was treated with K₂CO₃ (2.32 g, 16.8 mmol)and heated at reflux for 2 h. The reaction mixture was cooled to roomtemperature and MeOH was removed under reduced pressure. The aqueousresidue was extracted with EtOAc (2×200 mL). The combined organicextracts were washed with H₂O (1×100 mL), brine (1×100 mL), dried(Na₂SO₄) and concentrated under reduced pressure to give Int-4, inquantitative yield, as a yellow solid.

A mixture of thiolactam (example I-28, 400 mg, 1.03 mmol),DL-1-amino-2-propanol (0.64 mL, 620 mg, 8.24 mmol) and THF (5 mL) wereused according to the general procedure set forth for example 1b-1 inthe Examples section. The product was purified by flash chromatography,elution with 3:7 hexane-EtOAc, to provide 300 mg (68%) of the titlecompound as a mixture of diastereomers: ¹H NMR (400 MHz, CDCl₃) δ 7.40(m, 2H), 7.34 (d, 1H, J=8.8 Hz), 7.17 (m, 2H), 7.07 (m, 2H), 5.62 (m,1H), 4.02 (m, 1H), 3.68 (s, 3H), 3.27 (m, 3H), 2.79 (m, 1H), 2.44 (m,3H), 1.20 (m, 3H).

The following intermediates were prepared according to the method setforth above:

76%; ¹H NMR (400 MHz, CDCl₃) δ 7.36 (m, 3H), 7.15 (m, 4H), 5.21 (s, 1H),3.65 (m, 6H), 3.23 (m, 1H), 2.80 (m, 1H), 2.41 (m, 3H), 1.24 (m, 3H).

58%; ¹H NMR (400 MHz, CDCl₃) δ 7.42 (m, 2H), 7.35 (dd, 1H, J=2.4, 8.8Hz), 7.13 (m, 4H), 5.94 (d, 1H, J=5.6 Hz), 4.23 (br s, 1H), 3.97 (m,1H), 3.83 (d, 2H, J=4.8 Hz), 3.68 (m, 5H), 3.28 (dd, 1H, J=3.6, 10.4Hz), 3.08 (br s, 1H), 2.76 (m, 1H), 2.47 (m, 3H); MS (ES) m/z 448 (M⁺).

66%; ¹H NMR (300 MHz, CDCl₃) δ 7.47 (m, 3H), 7.24 (m, 2H), 7.14 (m, 2H),5.99 (br s, 1H), 3.81 (m, 1H), 3.72 (s, 3H), 3.62 (m, 2H), 3.53 (m, 2H),3.30 (m, 1H), 2.80 (m, 1H), 2.50 (m, 3H); MS (CI) m/z 448 (M+H)⁺.

A solution of thione (Ex. I-30, 255 mg, 0.68 mmol) andDL-1-amino-2-propanol (0.53 mL, 6.80 mmol) in THF (6 mL) was heated atreflux for 18 h, cooled to room temperature, and concentrated underreduced pressure. The residue was diluted with EtOAc (ca. 50 mL), washedwith saturated aqueous NaHCO₃ (1×10 mL), H₂O (3×10 mL), saturatedaqueous NaCl (1×10 mL), dried (Na₂SO₄), and concentrated under reducedpressure. Purification by flash chromatography, elution with 3:1hexane-acetone, gave 198 mg (70%) of the amidine as a foam; ESIMS 415(M+H, base).

The following intermediates were prepared according to the method setforth above:

36%; ESIMS 415 (M+H, base).

38%; MS (ESI) m/z 430 (M⁺).

35%; MS (ESI) m/z 430 (M⁺).

Condensed with 3-amino-2-butanol (J. Org. Chem. 1977, 42, 3541) 56%(mixture of diastereomers); ¹H NMR (300 MHz, CDCl₃) δ 8.65 (d, 1H, J=4.5Hz), 7.81 (m, 2H), 7.34 (m, 2H), 7.18 (m, 2H), 5.30 (m, 1H), 3.90 (m,1H), 3.76 (m, 1H), 3.70 (m, 3H), 3.32 (m, 1H), 2.77 (m, 1H), 2.50 (m,3H), 1.24 (m, 3H), 1.24 (m, 3H), 1.11 (m, 3H); MS (ES) m/z 428 (M⁺).

27%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.52 (d, 1H, J=4.8 Hz), 7.91 (m, 2H),7.45 (t, 1H, J=6 Hz), 7.36 (dd, 1H, J=2.4, 8.8 Hz), 7.08 (m, 3H), 4.73(t, 1H, J=5.6 Hz), 3.57 (s, 3H), 3.48 (m, 2H), 3.18 (m, 2H), 2.5 (m,2H), 2.24 (m, 2H); MS (ESI) m/z 401 (M⁺).

A solution of the lactam (Ex. I-10, 7.31 g, 18.2 mmol) in THF (21 mL)was added to a suspension of NaH (870 mg of 60% oil dispersion, 21.8mmol) in THF (70 mL) at 0° C. The reaction mixture was stirred at 0° C.for 30 min, warmed to room temperature and stirred for 30 min, thencooled to 0° C.(Dimorpholino)phosphorochloridate (6.48 g, 25.5 mmol) was added, themixture was allowed to warm to room temperature over 4.5 h, and themixture was filtered with additional THF (ca. 10 mL). A mixture of thefiltrate and DL-1-amino-2-propanol (2.80 mL, 36.4 mmol) was stirred atroom temperature for 18 h and concentrated under reduced pressure. Theresidue was diluted with EtOAc (ca. 250 mL), washed with saturatedaqueous NaHCO₃ (1×75 mL), H₂O (2×75 mL), saturated aqueous NaCl (1×75mL), dried (Na₂SO₄), and concentrated under reduced pressure.Purification by flash chromatography, elution with 19:1 EtOAc-MeOH, gave3.06 g (37%) of Int-15 as a foam; ESIMS 459 (M+H, base).

Benzodiazepinone I-1 (510 mg) was dissolved in dioxane (6 mL) and cooledto 0° C. To this was added 4 mL 1M aqueous LiOH. The mixture was stirredat 0° C. until TLC indicated complete reaction. The mixture wasacidified with 1 M H₃PO₄ and extracted with ethyl acetate (3×). Thecombined organic layers were washed with brine, dried over magnesiumsulfate, filtered, and concentrated under reduced pressure to affordInt-16 as a tan powder (400 mg).

In a dry flask under nitrogen atmosphere was placed DMF (60 mL),tert-butylisocyanoacetate (0.69 mL, 4.5 mmol) and iminophosphate(Int-19, 1.44 g, 2.82 mmol). The contents were cooled to 0° C. and thentreated with potassium tert-butoxide (0.532 g, 4.50 mmol). The resultingpurple solution was stirred at 0° C. for thirty minutes then poured intoa flask containing 100 mL of a 5% acetic acid solution. The aqueouslayer was extracted with ethyl acetate and the extracts were washedthree times with water. The organics were dried over magnesium sulfate,filtered and concentrated. The residue was purified by flashchromatography through silica gel to yield Int-17 (1.35 g, 2.70 mmol) in95% yield. ¹H NMR (CDCl₃): 7.90(s, 1H), 7.50-7.60(m, 3H), 7.44(m, 1H),7.20-7.26(m, 2H), 7.03(t, 1H, J=9.3 Hz), 6.50(dd, 1H, J=6.7, 9.3 Hz),3.55(s, 3H), 2.32-2.46(m, 2H), 1.85-2.00(m, 2H), 1.60(s, 9H).MS(ES+)=498(10%, M+), 520(80%, M+22).

Benzodiazepinone I-3 (1.25 g, 3.0 mmol) was added to a suspension of NaH(3.3 mmol) in THF (10 mL). The resulting solution was stirred for 10 minand bis-morpholinophosphorochloridate (762 mg, 3.0 mmol; Ning et al., J.Org. Chem. 1976, 41, 2720-2724) was added. After 1 h an additional 100mg of the phosphoryl chloride was added. The mixture was stirred for 1 hand filtered. The filtrate was concentrated and the residue waschromatographed on silica gel (graded elution with 4:1 CH₂Cl₂:ether and8:1:1 CH₂Cl₂:ethyl acetate:methanol) to afford 1.3 g of theiminophosphate Int-18 as a white foam.

The following intermediate was prepared according to the method setforth above in Int-18, using Example I-1 as the startingbenzodiazepinone:Synthesis of Compounds of Formula Ia

EXAMPLE I-1 Methyl3-[(3S)-7-chloro-5-(2-fluorophenyl)-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]propanoate

A mixture of 2-amino-5-chloro-2′-fluorobenzophenone (24.9 g, 99.7 mmol),the acid chloride (Int-1, 41.7 g, 104 mmol), and CHCl₃ (100 mL) wereheated at reflux for 30 min and then allowed to cool to RT. Ether (600mL) was added causing a precipitate to form. The reaction mixture wascooled to 0° C. for 15 min, and the solid was collected and washed withadditional portions of ether. The solid was dried in vacuo to provide55.4 g (90%) of amide. ¹H NMR (CDCl₃, 300 MHz) δ 8.70 (d, 2H, J=9.2 Hz),7.74 (d, 2H, J=11.2 Hz), 7.62 (m, 4H), 7.46 (s, 1H), 7.37 (m, 2H), 7.26(m, 3H), 7.17 (m, 1H), 5.80 (d, 1H, J=6 Hz), 4.48 (m, 2H), 4.34 (m, 1H),4.24 (m, 1H), 3.68 (s, 3H), 2.55 (m, 3H), 2.14 (m, 1H).

A mixture of the amide (42 g, 68 mmol) and Et₃N (170 mL) in CH₂Cl₂ (170mL) was stirred at 40° C. overnight. The reaction mixture wasconcentrated under reduced pressure and the residue was dried in vacuofor 5 min to provide an oil. To this oil were added HOAc (35 mL) and1,2-dichloroethane (665 mL) and the mixture was stirred at 40° C.overnight. The reaction mixture was concentrated under reduced pressureand the residue was dissolved in CH₂Cl₂, slurried onto silica gel anddried to a free-flowing powder. The silica gel was washed with severalportions of hexane, which were discarded, and then with several portionsof 9:1 CH₂Cl₂:CH₃OH. The CH₂Cl₂/CH₃OH washings were combined andconcentrated under reduced pressure to provide an oil. Ether was addedto the oil to give a white solid which was filtered, washed with severaladditional portions of ether and dried in vacuo to provide 14 g (55%) ofthe title compound. ¹H NMR (300 MHz, CDCl₃) δ 8.94 (br s, 1H), 7.54 (m,1H), 7.45 (m, 1H), 7.23 (m, 1H), 7.20 (d, 1H, J=2.4 Hz), 7.12 (d, 1H,J=8.8 Hz), 7.06 (m, 1H), 3.67 (m, 4H), 2.68 (m, 2H), 2.60 (m, 1H), 2.51(m, 1H).

The following compounds were prepared according to the general procedureset forth above in Example I-1. Any modifications in starting materialsor conditions that are required for the synthesis of a particularexample will be readily apparent to one skilled in the art of organicsynthesis. For example, in the synthesis of the compound of example I-2,it should be readily apparent that the amino acid chloride required forthe synthesis derives from L-aspartic acid.

EXAMPLE I-2

¹H NMR (300 MHz, DMSO) δ 11.0 (bs, 1H), 4.05 (t, 1H), 3.7 (s, 3H). MS(ES+): 361 (M+1)⁺.

EXAMPLE I-3

¹H NMR (400 MHz, CDCl₃) δ 8.74 (bs, 1H), 7.61-7.43 (m, 3H), 3.67 (s,3H), 2.70-2.49 (m, 4H).

EXAMPLE I-4

¹H NMR (400 MHz, CDCl₃) δ 9.08 (bs, 1H), 7.58-7.03 (m, 7H), 3.67 (s,3H), 2.74-2.44 (m, 4H).

EXAMPLE I-5

¹H NMR (400 MHz, DMSO-d₆) δ 10.78 (bs, 1H), 5.04 (s, 2H), 3.55 (m, 1H)

EXAMPLE I-6

¹H NMR (400 MHz, DMSO) δ 10.9 (bs, 1H), 5.1 (s, 2H), 4.05 (t, 1H). MS(ES+): 437 (M+1)⁺.

EXAMPLE I-7

¹H NMR (300 MHz, CDCl₃) δ 9.04 (bs, 1H), 3.72 (m, 1H), 3.66 (s, 3H). MS(ES): 391 (M+1)⁺.

EXAMPLE I-8

¹H NMR (300 MHz, CDCl₃) δ 8.5 (bs, 1H), 3.7 (s, 3H), 3.6 (m, 1H). MS(ES): 389 (M+1)⁺.

EXAMPLE I-9

¹H NMR (400 MHz, CDCl₃) δ 8.59 (d, J=4.6 Hz, 1H), 8.07 (d, J=7.9 Hz,1H), 7.80 (comp, 2H), 7.46 (dd, J=8.6, 2.4 Hz, 1H), 7.35 (m, 2H), 7.30(comp, 5H), 7.01 (d, J=8.6 Hz, 1H), 5.10 (s, 2H), 3.75 (dd, J=5.8, 4.0Hz, 1H), 2.73 (dd, J=7.1 Hz, 2H), 2.56 (m, 2H); ESIMS 456 (M+Na), 434(M+H, base); Anal. Calcd. for C₂₄H₂₀ClN₃O₃.0.25H₂O: C, 65.75; H, 4.71;N, 9.59. Found: C, 65.65; H, 4.96; N, 9.19.

EXAMPLE I-10

¹H NMR (400 MHz, CDCl₃) δ 8.60 (d, J=4.6 Hz, 1H), 8.09 (comp, 2H), 7.82(ddd, J=7.8, 7.8, 1.3 Hz, 1H), 7.60 (dd, J=8.6, 2.2 Hz, 1H), 7.53 (d,J=2.2 Hz, 1H), 7.37 (dd, J=7.2, 5.0 Hz, 1H), 6.98 (d, J=8.6 Hz, 1H),3.76 (dd, J=7.5, 5.9 Hz, 1H), 3.67 (s, 3H), 2.67 (m, 2H), 2.56 (m, 2H);ESIMS 424 (M+Na), 402 (M+H, base).

EXAMPLE I-11

38%; ¹H NMR (400 MHz, CDCl₃) δ 8.58 (d, J=4.6 Hz, 1H), 8.07 (d, J=7.8Hz, 1H), 7.94 (s, 1H), 7.80 (ddd, J=7.8, 7.8, 1.6 Hz, 1H), 7.52 (dd,J=8.6, 2.4 Hz, 1H), 7.37 (m, 2H), 7.02 (d, J=8.6 Hz, 1H), 3.75 (dd,J=7.6, 5.6 Hz, 1H), 3.65 (s, 3H), 2.66 (m, 2), 2.53 (m, 2H).

EXAMPLE I-12

¹H NMR (300 MHz, CDCl₃) δ 9.0 (bs, 1H), 3.6 (m, 1H), 1.4 (s, 9H). MS(ES): 431 (M+1)⁺.

EXAMPLE I-13

Nitronium tetrafluoroborate (4.85 mL of a 0.5 M solution in sulfolane,2.43 mmol) was added to a solution of the A-ring unsubstitutedbenzodiazepine (501 mg, 1.47 mmol) in CH₃CN (7.4 mL) at 0° C. Thereaction mixture was allowed to warm to RT overnight and quenched byaddition of H₂O. The reaction mixture was diluted with EtOAc, washedwith saturated aqueous NaHCO₃, H₂O, brine, dried (Na₂SO₄), andconcentrated under reduced pressure to give an oil. Purification byflash chromatography, elution with 55:45 hexane-EtOAc, provided theproduct in sulfolane. This material was partitioned between ether andH₂O, the layers were separated, and the aqueous layer was extracted withether. The combined ether layers were washed with H₂O (3×), brine, dried(MgSO₄) and concentrated to provide the title compound as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.31 (s, 1H), 7.92 (d, 1H),7.65-7.55 (m, 2H), 3.57 (s, 3H), 2.63-2.17 (m, 4). MS (AP+) calcd.MH+386, found 386; (AP−) calcd. [M−H]-384, found 384.

EXAMPLE I-14

Example I-14 was prepared from the corresponding methyl ester (ExampleI-11) using the following transesterification procedure (Otera, J. etal. J. Org. Chem. 1991, 56, 5307):

A mixture of the methyl ester (1 eq.), propyl alcohol (4-5 eq.), andbis(dibutylchlorotin) oxide (0.1 eq.) in PhCH₃ (0.1 M) was heated atreflux until the reaction was judged complete by TLC. The reactionmixture was allowed to cool to room temperature and was concentratedunder reduced pressure. Purification by flash chromatography, elutionwith hexane-EtOAc, delivered the desired propyl ester (90%). ESIMS 408(M+Na, base), 386 (M+H); Anal. Calcd. for C₂₀H₂₀ClN₃O₃: C, 62.26; H,5.22; N, 10.89. Found: C, 62.00; H, 5.32; N, 10.69.

The following compounds were prepared according to the general procedureset forth above in example I-14, using the appropriate methyl ester asthe starting material.

EXAMPLE I-15

66%; ESIMS 394 (M+Na, base), 372 (M+H); Anal. Calcd. forC₂₁H₂₂ClN₃O₃-0.25H₂O: C, 60.64; H, 4.96; N, 11.17. Found: C, 60.54; H,5.01; N, 10.96.

EXAMPLE I-16

¹H NMR (CDCl₃, 400 MHz) δ 8.85 (bs, 1H), 8.57 (d, 2H), 5.13 (s, 2H).

EXAMPLE I-17

¹H NMR (CDCl₃, 400 MHz) δ 8.38 (bs, 1H), 4.05 (t, 2H), 1.37-1.32 (m,2H), 0.89 (t, 3H). ESIMS 439 (M+Na), 417 (M+H, base).

EXAMPLE I-18

91%; ESIMS 422 (M+Na, base), 400 (M+H); Anal. Calcd. for C₂₁H₂₂ClN₃O₃:C, 63.08; H, 5.55; N, 10.51. Found: C, 62.83; H, 5.59; N, 10.44.

EXAMPLE I-19

88%; ESIMS 422 (M+Na, base), 400 (M+H); Anal. Calcd. for C₂₁H₂₂ClN₃O₃:C, 63.08; H, 5.55; N, 10.51. Found: C, 62.82; H, 5.65; N, 10.36.

EXAMPLE I-20

Prepared by Fisher esterification (ethanol, TFA) of the correspondingcarboxylic acid (Int-16). ¹H NMR (400 MHz, CDCl₃) δ 8.54 (bs, 1H), 4.2(m, 3H), 1.3 (t, 3H).

EXAMPLE I-21

Prepared by Fisher esterification (2-propanol, trace conc. H₂SO₄) of thecorresponding carboxylic acid (Int-16). ESIMS 403 (M+H, base).

EXAMPLE I-22

Benzodiazepine I-1 (308 mg, 0.82 mmol) was added to a stirringsuspension of NaH (39 mg, 0.98 mmol) in DMF (8 mL). The resultingmixture was heated to 70° C. for 15 min at which time a homogeneoussolution formed. To this solution was added 2-chloroethyl-diethylamine(270 mg, 1.6 mmol). The resulting solution was stirred for 30 min andpartitioned between ethyl acetate and H₂O. The organic phase was washedwith saturated H₂O and saturated aq NaCl, dried (Na₂SO₄), andconcentrated under reduced pressure. Silica gel chromatography (95:5,chloroform:methanol) provided the desired compound as a yellow oil(88%). ¹H NMR (CDCl₃, 400 MHz) δ 4.39-4.31 (m, 1H), 3.64 (s, 3H), 0.99(t, 6H). ESIMS 474 (M+H, base).

The following compounds were prepared according to the general procedureset forth above in Example I-22. Any modifications in starting materialsor conditions that are required for the synthesis of a particularexample will be readily apparent to one skilled in the art of organicsynthesis.

EXAMPLE I-23

¹H NMR (CDCl₃, 400 MHz) δ 3.65 (s, 3H), 3.43 (s, 3H).

EXAMPLE I-24

¹H NMR (CDCl₃, 400 MHz) δ 5.21-5.11 (dd, 2H), 4.14 (t, 1H), 3.41 (s,3H).

EXAMPLE I-25

¹H NMR (CDCl₃, 400 MHz) δ 5.07 (s, 2H), 4.37-4.30 (m, 1H), 3.77 (m, 1H),3.64 (m, 1H). ESIMS 550 (M+H, base).

EXAMPLE I-26

The 3-amino-benzodiazepine (J. Med. Chem. 1968, 11, 457; 0.15 g, 0.47mmol) and DMF (4 mL) were added to a round-bottom flask and cooled to 0°C. Triethylamine (0.07 mL, 0.05 g, 0.52 mmol) was added to the reactionmixture followed by dropwise addition of methyl bromoacetate (0.04 mL,0.07 g, 0.47 mmol). The reaction was allowed to warm to RT over 4 h.When the reaction was judged to be complete, the mixture was poured intoa separatory funnel containing ethyl acetate and water. The organiclayer was collected and was washed with water, saturated aqueous brine,dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theproduct was isolated by flash chromatography using 4:1 ethylacetate/hexanes as eluant to provide compound I-26 as white solid (57%).¹H NMR (300 MHz, DMSO-d₆) δ 11.0 (s, 1H), 7.59 (m, 5H), 7.29 (d, 1H, J=9Hz), 6.98 (d, 1H, J=2.4 Hz), 4.41 (s, 1H), 3.65 (m, 2H), 3.63 (s, 3H),3.22 (bs, 1H). MS (ES): 392 (M⁺).

EXAMPLE I-27

The 3-amino-benzodiazepine (J. Med. Chem. 1968, 11, 457; 0.15 g, 0.47mmol) and ethanol (3 mL) were combined in a round bottom flask. Methylacrylate (0.05 mL, 0.05 g, 0.52 mmol) was added and the reaction mixturestirred for 5 d at 20° C. The reaction mixture was poured into aseparatory funnel containing ethyl acetate and water. The organic layerwas collected and was washed with water, saturated aqueous brine, driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theproduct was isolated by flash chromatography using 4:1 ethylacetate/hexanes as eluant to provide I-27 as white solid (12%). ¹H NMR(400 MHz, DMSO-d₆) δ 10.88 (s, 1H), 7.58 (dd, 1H, J=2.4, 8.8 Hz), 7.49(m, 4H), 7.22 (d, 1H, J=8.8 Hz), 6.93 (d, 1H, J=2.4 Hz), 4.23 (s, 1H),3.54 (s, 3H), 3.09 (bs, 1H), 2.86 (bs, 2H), 2.60 (m, 1H). MS (ES): 406(M⁺).

EXAMPLE I-28

A suspension of the benzodiazepinone (Example I-1, 16.95 g, 45.32 mmol),Lawesson's reagent (21.97 g, 54.32 mmol) and PhCH₃ (200 mL) was heatedat 100° C. After 30 min, the reaction became homogeneous, was judged tobe complete and was allowed to cool to RT causing a precipitate to form.Ether (400 mL) was added, causing additional precipitate to form, andthe mixture was filtered. Silica gel was added to the filtrate and thismixture was concentrated under reduced pressure to give a free-flowingpowder. The silica gel was slurried in CH₂Cl₂, filtered, and thefiltrate was concentrated under reduced pressure to give a yellowviscous oil. Ether was added to the oil to precipitate a pale yellowsolid that was filtered, washed with several additional portions ofether, and dried in vacuo to provide 11.47 g (65%) of I-28 as a yellowsolid. ¹H NMR (CDCl₃, 300 MHz) δ 10.1 (br s, 1H), 7.60 (t, 1H, J=7.4Hz), 7.51 (m, 2H), 7.21 (m, 2H), 7.19 (d, 1H, J=8.4 Hz), 7.15 (t, 1H,J=9.3 Hz), 3.95 (m, 1H), 3.69 (s, 3H), 2.86 (m, 1H), 2.68 (m, 3H).

The following example was prepared according to the procedure set forthabove in example I-28:

EXAMPLE I-29

MS (ES): 408 (M+1)⁺.

EXAMPLE I-30

A mixture of benzodiazepinone Ex I-11 (1.00 g, 2.80 mmol) and Lawesson'sreagent (1.13 g, 2.80 mmol) in PhCH₃ (19 ml) was heated at reflux for 2h, cooled to room temperature, and concentrated under reduced pressure.The residue was purified immediately by flash chromatography, elutionwith 50:1 CH₂Cl₂:MeOH, to give 260 mg (25%) of thione as a foam; ¹H NMR(400 MHz, DMSO-d₆) δ 12.58 (s, 1H), 8.55 (d, J=4.4 Hz, 1H), 8.03 (d,J=7.9 Hz, 1H), 7.95 (m, 1H), 7.65 (dd, J=8.8, 2.4 Hz, 1H), 7.51 (dd,J=6.4, 5.0 Hz, 1H), 7.37 (comp, 2H), 3.83 (m, 1H), 3.58 (s, 3H), 2.52(m, 4H).

EXAMPLE I-31

Benzodiazepinone Ex I-1 (374 mg, 1 mmol) was dissolved in CH₂Cl₂ (7 mL).To this was added mCPBA (393 mg, 2.3 mmol) in one portion. The mixturewas stirred for 18 h, diluted with CH₂Cl₂ (50 mL), washed with satNaHCO₃ and brine. The organic layer was dried over magnesium sulfate,filtered, and concentrated. The residue was purified immediately byflash chromatography, elution with 95:5 CH₂Cl₂:MeOH, to give 289 mg ofthe N-oxide as a white solid (74%). ¹H NMR NMR (CDCl₃, 400 MHz) δ 9.02(br s, 1H), 4.50 (m, 1H). ESIMS 413 (M+Na, base).

Synthesis of Compounds of Formula Ib

Compounds of formula (1b) may be prepared from the correspondingthiolactam of formula (1a) wherein R⁴ is hydrogen and R⁵, R⁶═S) by thefollowing general methods.

General Procedure 1: the Addition of Amines to Thiolactam to ProduceAmidines.

The Thiolactam, the appropriate amine (5-20 mmol/mmol of thiolactam),and either tetrahydrofuran (THF, 2-10 mL/mmol of thiolactam) or1,4-dioxane (dioxane, 2-10 mL/mmol of thiolactam) were combined andheated to 50° C. (THF) or 95° C. (dioxane) for 2-72 h. When the reactionwas judged by TLC to be complete, the reaction mixture was allowed tocool to RT. The solvents were removed in vacuo and, in some cases, theresidue was directly chromatographed on silica gel to provide thedesired amidine. In other cases, the remaining residue was dissolved inan appropriate solvent (EtOAc, for example) and the product was washedwith H₂O, brine, dried (MgSO₄ or CaSO₄), filtered and the solvents wereagain removed under reduced pressure and the residue was chromatographedon silica gel to provide the desired amidine of Formula Ib.

The following compounds were prepared according to the general procedureabove. Any modifications in starting materials or conditions that arerequired for the synthesis of a particular example will be readilyapparent to one skilled in the art of organic synthesis.

EXAMPLE Ib-1 Methyl3-[(3S)-7-chloro-5-(2-fluorophenyl)-2-(methylamino)-3H-1,4-benzodiazepin-3-yl]propanoate

¹H NMR (400 MHz, CDCl₃) δ 7.43-7.05 (m, 7H), 5.20 (bs, 1H), 3.68 (s,3H), 2.87 (d, 3H), 2.51-2.30 (m, 3H). MS (ESI) m/z 388 (M+H)⁺, base.

EXAMPLE Ib-2

¹H NMR (400 MHz, CDCl₃) δ 8.82 (d, 1H), 8.43 (t, 1H), 8.14 (d, 1H), 7.97(m, 1H), 7.80 (dd, 1H), 7.64 (m, 2H), 4.17 (dd, 1H), 3.65 (s, 3H), 3.14(s, 3H), 2.84-2.36 (m, 4H). MS (AP+) m/z 371 (M+H)⁺.

EXAMPLE Ib-3

23%; ¹H NMR (400 MHz, CDCl₃) δ 7.52-7.06 (m, 7H), 5.00 (bs, 1H), 3.70(s, 3H), 3.52-3.22 (m, 3H), 2.80 (m, 1H), 2.57-2.33 (m, 3H), 1.21 (t,3H).

EXAMPLE Ib-4

32%; ¹H NMR (400 MHz, CDCl₃) δ 7.46-7.08 (m, 12H), 5.26 (bs, 1H), 4.68(dd, 1H), 4.47 (dd, 1H), 3.67 (s, 3H), 3.29 (m, 1H), 2.80 (m, 1H),2.52-2.31 (m, 3H). MS (ESI) m/z 464 (M+H)⁺, base.

EXAMPLE Ib-5

66%; ¹H NMR (CDCl₃₌, 400 MHz) δ 8.50 (d, 2H, J=6.0 Hz), 7.42 (m, 2H),7.34 (dd, 1H, J=8.7, 2.4 Hz), 7.25 (d, 1H, J=9.3 Hz), 7.14 (m, 2H), 7.11(m, 3H), 5.60 (br s, 1H), 4.60 (d, 2H, J=4.8 Hz), 3.68 (s, 3H), 3.30(dd, 1H, J=10.3, 3.1 Hz), 2,83 (m, 1H), 2.50 (m, 3H). MS (CI): 465(M+H)⁺.

EXAMPLE Ib-6

70%; ¹H NMR (CDCl₃, 300 MHz) δ 8.52 (d, 2H, J=6.0 Hz), 7.46 (m, 3H),7.27-7.10 (m, 6H), 5.28 (br s, 1H), 3.72 (br m, 5H), 3.28 (dd, 1H,J=9.9, 3.9 Hz), 2.98 (t, 2H, J=7.05 Hz), 2.70 (m, 1H), 2.48 (m, 2H),2.32 (m, 1H). MS (CI): 479 (M+H)⁺.

EXAMPLE Ib-7

84%; ¹H NMR (CDCl₃, 300 MHz) δ 7.45 (t, 2H, J=6.9 Hz), 7.38 (dd, 1H,J=8.8, 2.2 Hz), 7.23 (m, 2H), 7.12 (m, 2H), 5.16 (br s, 1H), 3.74 (s,3H), 3.30 (m, 3H), 2.85 (m, 1H), 2.50 (m, 3H), 1.92 (m, 1H), 0.98 (t,6H, J=7.0 Hz). MS (ES): 429 (M⁺).

EXAMPLE Ib-8

68%; ¹H NMR (CDCl₃, 300 MHz) δ 7.57 (s, 1H), 7.45 (m, 3H), 7.24 (m, 2H),7.14 (m, 2H), 6.82

EXAMPLE Ib-9

66%; ¹H NMR (CDCl₃, 400 MHz) δ 7.47 (m, 3H), 7.37 (m, 1H), 7.25 (t, 1H,J=7.2 Hz), 7.17 (m, 2H), 6.03 (br s, 1H), 3.85 (m, 3H), 3.74 (s, 3H),3.51 (m, 1H), 3.39 (m, 1H), 2.83 (m, 1H), 2.48 (m, 3H). MS (CI): 418(M+H)⁺.

EXAMPLE Ib-10

1.3 g of the iminophosphate Int-18 was dissolved in THF (10 mL) andtreated with CH₃NH₂ (6 mL of a 2M THF solution, 12 mmol). After 3 hoursthe mixture was filtered and concentrated to an oil. Trituration withdiisopropyl ether:hexanes provided Ib-10 as a white solid. ¹H NMR (400MHz, CDCl₃) δ 7.50-7.06 (m, 7H), 5.15 (d, 1H), 3.70 (s, 3H), 2.95 (d,3H), 2.79 (m, 1H), 2.53-2.31 (m, 3H).

Synthesis of Compounds of Formula Ic

General Procedure I: Swern Oxidation of Alcohols Using Oxalyl Chlorideas Activating Agent.

A round-bottom flask was equipped with a stir bar and flushed with N₂.To the flask were added CH₂Cl₂ (5-15 mL/mmol of alcohol), dry dimethylsulfoxide (DMSO, 3-4 mmol/mmol of alcohol) and the solution was cooledto −78° C. by means of a dry ice/acetone bath. Oxalyl chloride (2-3mmol/mmol of alcohol) was added dropwise to the DMSO solution, takingcare to maintain the reaction temperature below −50° C. When theaddition was complete, the resulting solution was allowed to stir at−78° C. for 30 min. The Alcohol was dissolved in CH₂Cl₂ (2-3 mL/mmol ofalcohol) and was carefully added to the DMSO solution at −78° C. Theresulting mixture was allowed to stir at −78° C. for 2 h. Triethylamine(5-11 mmol/mmol of alcohol) was added and the mixture was allowed towarm to RT. When the reaction was judged to be complete, the mixture waspoured into a separatory funnel containing water and CH₂Cl₂. The organiclayer was collected and was washed with water, saturated aqueous brine,dried over Na₂SO₄, filtered and the solvents were removed under reducedpressure to provide the desired product which, in most cases, was usedwithout further purification. If deemed necessary, the product wasfurther purified by flash chromatography on silica gel.

General Procedure II: Swern Oxidation of Alcohols Using TrifluoroaceticAnhydride as Activating Agent.

Anhydrous DMSO (3-4 mmol/mmol of alcohol) was added to CH₂Cl₂ (5-15mL/mmol of alcohol) and the solution was cooled to −78° C.Trifluoroacetic anhydride (2-3 mmol/mmol of alcohol) was added dropwiseto the DMSO solution, taking care to maintain the reaction temperaturebelow −50° C. When the addition was complete, the resulting solution wasstirred at −78° C. for 30 min. A solution of the Alcohol in CH₂Cl₂ (2-3mL/mmol of alcohol) was added carefully to the DMSO solution at −78° C.The reaction mixture was allowed to stir at −78° C. for 2 h, after whichtime it was allowed to warm to −35° C. for 5 min and was again cooled to−78° C. Et₃N (5-10 mmol/mmol of alcohol) was added and the stirring wascontinued at −78° C. for 30 min, after which time the reaction mixturewas allowed to warm to RT. When the reaction was judged to be complete,the mixture was poured into a separatory funnel containing H₂O andCH₂Cl₂ and the layers were separated. The organic layer was washed withH₂O, brine, dried (MgSO₄), filtered and the solvents were removed underreduced pressure to provide the desired product which, in most cases,was used without further purification. If deemed necessary, the productwas purified by flash chromatography on silica gel.

EXAMPLE Ic-1

A mixture of alcohol (Example Ib-9, 200 mg, 0.48 mmol), DMSO (0.12 mL,130 mg, 1.70 mmol), trifluoroacetic anhydride (0.12 mL, 180 mg, 0.84mmol), CH₂Cl₂ (5 mL) and Et₃N (0.77 mL, 560 mg, 5.52 mmol) were usedaccording to general procedure II. The product was purified by flashchromatography, elution with 1:1 hexane-EtOAc, to provide 70 mg (35%) ofIc-1 as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.63 (m, 2H), 7.49 (m,3H), 7.27 (m, 3H), 7.06 (t, 1H, J=9.3 Hz), 4.13 (m, 1H), 3.70 (s, 3H),2.86 (m, 4H); MS (ES) m/z 398 (M+H)⁺.

EXAMPLE Ic-2

A mixture of alcohol (Int-5, 160 mg, 0.37 mmol), DMSO (90 μL, 0.10 g,1.30 mmol), trifluoroacetic anhydride (90 μL, 0.14 g, 0.65 mmol), CH₂Cl₂(5 mL) and Et₃N (0.60 mL, 0.43 g, 4.26 mmol) were used according togeneral procedure II. The resulting ketone closed to the imidazoleduring purification by flash chromatography, elution with 3:7hexane-EtOAc, provide 50 mg (36%) of Ic-2 as a white solid: ¹H NMR (400MHz, DMSO-d₆) δ 7.64 (t, 1H, J=7.4 Hz), 7.54 (dd, 1H, J=2.4, 8.8 Hz),7.31 (m, 4H), 6.99 (t, 1H, J=9.3 Hz), 6.88 (s, 1H), 3.98 (m, 1H), 3.64(s, 3H), 2.79 (m, 4H), 2.33 (s, 3H); MS (ESI) m/z 412 (M+H)⁺.

EXAMPLE Ic-3

A mixture of alcohol (Int-6, 250 mg, 0.57 mmol), DMSO (0.14 mL, 160 mg,2.00 mmol), trifluoroacetic anhydride (0.14 mL, 210 mg, 1.00 mmol),CH₂Cl₂ (5 mL) and Et₃N (0.92 mL, 670 mg, 6.60 mmol) were used accordingto general procedure II. The product was purified by flashchromatography, elution with 3:7 hexane-EtOAc, to provide 50 mg (22%) ofIc-3 as a pale yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 7.59 (t, 1H,J=7.4 Hz), 7.52 (dd, 1H, J=2.2, 8.6 Hz), 7.41 (q, 2H, J=5.2, 13.6 Hz),7.27 (d, 1H, J=2.0 Hz), 7.21 (m, 1H), 7.07 (s, 1H), 6.99 (m, 1H), 3.99(m, 1H), 3.64 (s, 3H), 2.79 (m, 4H), 2.27 (s, 3H); MS (ESI) m/z 412(M+H)⁺.

EXAMPLE Ic-4

A mixture of diol (Int-7, 2.01 g, 4.49 mmol), TIPSCl (1.15 mL, 1.04 g,5.39 mmol) Et₃N (0.69 mL, 500 mg, 4.94 mmol), and DMAP (60 mg, 0.45mmol) in CH₂Cl₂ (20 mL) was stirred for 4-6 h. When the reaction wasjudged to be complete, the reaction mixture was poured into EtOAc,washed with H₂O (2×), brine, dried (Na₂SO₄), filtered and concentratedunder reduced pressure. The product was isolated by flashchromatography, elution with CH₂Cl₂:MeOH (gradient 100:0-98:2), toprovide 1.25 g (46%) of the silylether as an orange oil: ¹H NMR (400MHz, CDCl₃) δ 7.42 (m, 2H), 7.34 (dd, 1H, J=2.4, 8.8 Hz), 7.13 (m, 4H),6.03 (bs, 1H), 4.02 (m, 2H), 3.84 (s, 3H), 3.67 (s, 3H), 3.26 (m, 1H),2.77 (m, 1H), 2.47 (m, 3H), 1.02 (m, 21H); MS (ESI) m/z 604 (M⁺).

A mixture of the silyl ether (1.25 g, 2.07 mmol), DMSO (0.59 mL, 650 mg,8.28 mmol), (COCl)₂ (0.36 mL, 530 mg, 4.14 mmol), CH₂Cl₂ (15 mL) andEt₃N (3.20 mL, 2.30 g, 22.77 mmol) were used according to generalprocedure I. The product was purified by flash chromatography, elutionwith using CH₂Cl₂:MeOH (gradient, 100:0-95:5), to provide 1.05 g (87%)of the imidazole-silyl ether as an orange oil: MS (ESI) m/z 584 (M⁺). Amixture of this silyl ether (1.05 g, 1.79 mmol) and TBAF (2.05 mL of a1.0 M solution in THF, 2.05 mmol) in THF (20 mL) was stirred for 1 h.When the reaction was judged to be complete, the mixture was poured intoEtOAc, washed with H₂O, brine, dried (Na₂SO₄), filtered and concentratedunder reduced pressure. The resulting yellow oil was treated withpentane to provide 500 mg (72%) of Ic-4 as a yellow solid: ¹H NMR (400MHz, DMSO-d₆) δ 7.76 (s, 2H), 7.66 (s, 1H), 7.54 (m, 2H), 7.29 (m, 2H),7.17 (t, 1H, J=9.6 Hz), 5.02 (m, 1H), 4.36 (m, 2H), 4.03 (m, 1H), 3.56(s, 3H), 2.61 (m, 4H); MS (ESI) m/z 427 (M⁺).

EXAMPLE Ic-5

A mixture of diol (Int-8, 360 mg, 0.80 mmol), DMF (4 mL), CH₂Cl₂ (2 mL),Et₃N (0.2 mL, 150 mg, 1.43 mmol), and DMAP (10 mg, 0.12 mmol) was cooledto 0° C. and TBS-Cl chloride (190 mg, 1.27 mmol) was added as a solid inone portion. The reaction mixture was stirred at 0° C. for 2 h. Thereaction mixture was poured into EtOAc, washed with H₂O, brine, dried(MgSO₄), filtered, and concentrated under reduced pressure to provide340 mg (75%) of the monosilyl ether (primary hydroxyl) as a yellow foam:MS (CD m/z 562 (M+H)⁺. The silyl ether (340 mg, 0.60 mmol), DMSO (0.17mL, 190 mg, 2.39 mmol), trifluoroacetic anhydride (0.17 mL, 250 mg, 1.20mmol), CH₂Cl₂ (8 mL) and Et₃N (0.95 mL, 690 mg, 6.82 mmol) were usedaccording to general procedure II. The product was purified by flashchromatography, elution with 1:1 hexane-EtOAc, to provide 140 mg (41%)of the ketone as a white solid: MS (CI) m/z 560 (M+H)⁺. A mixture ofthis ketone (130 mg, 0.232 mmol), DMF (4 mL) and p-toluenesulfonic acidmonohydrate (30 mg, 0.14 mmol) was heated to 80° C. for 4 h, after whichtime the reaction was judged to be complete and was allowed to cool toRT. The mixture was poured into EtOAc, washed with H₂O, brine, dried(MgSO₄), filtered and concentrated under reduced pressure. The productwas purified by flash chromatography, elution with 95:5 CH₂Cl₂:CH₃OH, toprovide 70 mg (74%) of Ic-5 as a white solid: ¹H NMR (300 MHz, CDCl₃) δ8.10 (d, 1H, J=9.0 Hz), 7.65 (m, 2H), 7.46 (m, 1H), 7.34 (m, 2H), 7.20(s, 1H), 7.04 (t, 1H, J=9.6 Hz), 4.90 (dd, 1H, J=13.5, 3.6 Hz), 4.49(dd, 1H, J=13.3, 7.7 Hz), 4.10 (m, 1H), 3.70 (s, 3H), 2.83 (m, 4H), 1.81(m, 1H). Anal. Calcd for C₂₂H₁₉ClFN₃O₃: C, 61.76; H, 4.48; N, 9.82.Found: C, 61.85; H, 4.56; N, 9.73.

EXAMPLE Ic-6

A mixture of alcohol (Int-14, 402 mg, 1.06 mmol), DMSO (0.30 mL, 330 mg,4.24 mmol), (COCl)₂ (0.18 mL, 270 mg, 2.12 mmol), CH₂Cl₂ (7 mL) and Et₃N(1.60 mL, 1.20 g, 11.66 mmol) were used according to general procedureI. The product was isolated by flash chromatography, elution with using2:1 hexane-acetone, to provide 140 mg (35%) of Ic-6 as a pale yellowsolid: ¹H NMR (300 MHz, DMSO-d₆) δ 8.52 (d, 1H, J=4.8 Hz), 8.10 (d, 1H,J=7.8 Hz), 7.97 (t, 1H, J=7.8 Hz), 7.82 (m, 3H), 7.52 (m, 2H), 7.11 (s,1H), 4.18 (t, 1H, J=6.6 Hz), 3.64 (s, 3H), 2.71 (m, 4H).

The following examples were prepared according to General Procedure IIset forth above in example Ic-6:

EXAMPLE Ic-7

49%; ¹H NMR (400 MHz, CDCl₃) δ 8.56 (d, J=4.6 Hz, 1H), 8.17 (d, J=7.7Hz, 1H), 7.79 (dd, J=7.7, 1.6 Hz, 1H), 7.77 (d, J=1.6 Hz, 1H), 7.56 (dd,J=8.8, 2.4 Hz, 1H), 7.50 (d, J=2.4 Hz, 1H), 7.34 (comp, 2H), 6.86 9 s,1H), 4.04 (m, 1H), 3.67 (s, 3H), 2.79 (m, 4H), 2.34 (s, 3H); ESIMS 395(M+H, base); Anal. Cald. for C₂₁H₁₉ClN₄O₂. 0.5 MeOH: C, 62.85; H, 5.15;N, 13.64. Found: C, 62.99; H, 4.98; N, 13.54.

EXAMPLE Ic-8 Methyl3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propanoate

A solution of the C7-bromo-benzodiazepine Ex I-10 (7.31 g, 18.2 mmol) inTHF (21 mL) was added to a suspension of NaH (870 mg of 60% oildispersion, 21.8 mmol) in THF (70 mL) at 0° C. The reaction mixture wasstirred at 0° C. for 30 min, warmed to room temperature and stirred for30 min, then cooled to 0° C. Bis-morpholinophosphorochloridate (6.48 g,25.5 mmol) was added, the mixture was allowed to warm to roomtemperature over 4.5 h, and the mixture was filtered with additional THF(ca. 10 mL). A mixture of the filtrate and DL-1-amino-2-propanol (2.80mL, 36.4 mmol) was stirred at room temperature for 18 h and concentratedunder reduced pressure. The residue was diluted with EtOAc (ca. 250 mL),washed with saturated aqueous NaHCO₃ (1×75 mL), H₂O (2×75 mL), saturatedaqueous NaCl (1×75 mL), dried (Na₂SO₄), and concentrated under reducedpressure. Purification by flash chromatography, elution with 19:1EtOAc-MeOH, gave 3.06 g (37%) of the adduct as a foam; ESIMS 459 (M+H,base).

A mixture of DMSO (1.88 mL, 26.6 mmol) and oxalyl chloride (1.16 mL,13.3 mmol) in CH₂Cl₂ (40 mL) was stirred at −78° C. for 30 min. Asolution of the alcohol prepared above (3.05 g, 6.64 mmol) in CH₂Cl₂ (26mL) was added. The reaction mixture was warmed to −15° C. and stirred 1h, cooled to −78° C., treated with Et₃N (5.55 mL, 39.9 mmol), andallowed to warm to room temperature over 3 h. The mixture was dilutedwith EtOAc (ca. 500 mL), washed with saturated aqueous NaHCO₃ (1×100mL), H₂O (1×100 mL), saturated aqueous NaCl (1×100 mL), dried (Na₂SO₄),and concentrated under reduced pressure to give a foam. A mixture ofthis foam and a catalytic amount of p-toluenesulfonic acid was stirredat room temperature for 18 h, neutralized by the addition of saturatedaqueous NaHCO₃ and diluted with EtOAc (ca. 500 mL). The layers wereseparated and the organic phase was washed with saturated aqueous NaHCO₃(1×100 mL), H₂O (2×100 mL), saturated aqueous NaCl (1×100 mL), dried(Na₂SO₄), and concentrated under reduced pressure. Purification by flashchromatography, elution with 19:1 EtOAc-MeOH, gave 2.56 g (88%) of Ic-8as a foam; ¹H NMR (400 MHz, CDCl₃) δ 8.57 (d, J=4.6 Hz, 1H), 8.17 (dJ=7.8 Hz, 1H), 7.79 (dd, J=7.7, 6.2 Hz, 1H), 7.71 (dd, J=8.6, 2.2 Hz,1H), 7.64 (d, J=2.2 Hz, 1H), 7.34 (dd, J=7.5, 5.0 Hz, 1H), 7.30 (d,J=8.6 Hz, 1H), 6.86 (s, 1H), 4.05 (m, 1H), 3.67 (s, 3H), 2.80 (comp,4H), 2.34 (s, 3H); ESIMS 461 (M+Na, base), 439 (M+H); Anal. calcd. forC₂₁H₁₉BrN₄O₂.0.25H₂O: C, 58.63; H, 4.43; N, 12.62. Found: C, 56.88; H,4.43; N, 12.23.

Example Ic-8 was formulated in an aqueous vehicle at a concentration of10 mg/ml. Accordingly, 10 mg of compound (and 9 mg NaCl) was dissolvedin 0.63 ml of 0.1 N HCl. Slowly and while stirring, 0.37 ml of 0.1 NNaOH was added. Adjustments are made to the dose volume depending on thedose being administered.

The following example was prepared according to General Procedure I setforth above in example Ic-8:

EXAMPLE Ic-9

EXAMPLE Ic-10

49%; ¹H NMR (400 MHz, CDCl₃) δ 8.54 (d, J=4.8 Hz, 1H), 8.13 (d, J=7.8Hz, 1H), 7.79 (dd, J=7.8, 1.7 Hz, 1H), 7.55 (dd, J=8.6, 2.4 Hz, 1H),7.43 (comp, 2H), 7.33 (dd, J=6.8, 4.8 Hz, 1H), 7.03 (s, 1H), 4.08 (m,1H), 3.67 (s, 3H), 2.80 (m, 4H), 2.26 (s, 3H); ESIMS 395 (M+H, base);Anal. Cald. for C₂₁H₁₉ClN₄O₂.0.5 MeOH: C, 62.85; H, 5.15; N, 13.64.Found: C, 62.96; H, 5.13; N, 13.33.

The following example was prepared according to the procedure set forthin example Ic-4:

EXAMPLE Ic-11

51%; ¹H NMR (300 MHz, DMSO-d₆) δ 8.52 (d, 1H, J=4.8 Hz), 8.09 (d, 1H,J=7.8 Hz), 7.97 (t, 1H, J=7.6 Hz), 7.78 (m, 2H), 7.67 (s, 1H), 7.50 (m,2H), 5.05 (bs, 1H), 4.40 (s, 2H), 4.16 (m, 1H), 3.64 (s, 3H), 2.70 (m,4H); MS (ESI) m/z 410 (M⁺).

The following example was prepared according to the procedure set forthin Example Ic-5:

EXAMPLE Ic-12

45%; ¹H NMR (300 MHz, CDCl₃) δ 8.54 (d, 1H, J=4.5 Hz), 8.14 (d, 1H,J=7.8 Hz), 8.05 (d, 1H, J=8.7 Hz), 7.80 (t, 1H, J=7.8 Hz), 7.60 (dd, 1H,J=9, 2.4 Hz), 7.45 (d, 1H, J=2.4 Hz), 7.34 (m, 1H), 7.12 (s, 1H), 4.79(d, 1H, J=12.9 Hz), 4.45 (d, 1H, J=12.9 Hz), 4.10 (m, 1H), 3.67 (s, 3H),2.80 (m, 4H). MS (ES) m/z 410 (M⁺).

EXAMPLE Ic-13

A mixture of alcohol (Int-13, 620 mg, 1.43 mmol), DMSO (0.40 mL, 5.64mmol), trifluoroacetic anhydride (0.40 mL, 2.83 mmol), Et₃N (2.00 mL,14.4 mmol) and CH₂Cl₂ were used according to general procedure II. Theintermediate ketone was used without purification. A mixture of theketone and p-toluenesulfonic acid (80 mg, 0.42 mmol) in DMF (5 mL) washeated at 80° C. for 30 min. After the reaction was judged to becomplete, it was allowed to cool to RT and was poured into EtOAc, washedwith H₂O, brine, dried (MgSO₄), filtered and concentrated under reducedpressure. The product was purified by flash chromatography, elution with2:1 hexane-acetone, to provide 210 mg (41%) of Ic-13 as a tan solid: ¹HNMR (300 MHz, CDCl₃) δ 8.56 (d, 1H, J=4.8 Hz), 8.17 (d, 1H, J=8.1 Hz),7.78 (m, 1H), 7.55 (dd, 1H, J=8.7, 2.4 Hz), 7.49 (m, 1H), 7.31 (m, 2H),4.0 (m, 1H), 3.66 (s, 3H), 2.80 (m, 4H), 2.25 (s, 3H), 2.19 (s, 3H); MS(ESI): m/z 408 (M⁺).

EXAMPLE Ic-14

To a solution of thiolactam Ex I-29 (203 mg, 0.5 mmol) in CH₂Cl₂ (1 mL)was added trimethyloxonium tetrafluoroborate (74 mg, 0.8 mmol). Thesolution was stirred for 1 hr and diluted with CH₂Cl₂ (50 mL). Thesolution was washed with sat NaHCO₃ and brine, dried over MgSO₄,filtered, and concentrated. Flash chromatography (4:1 hexanes:ethylacetate) provided 112 mg of the methylthioimidate as a white foam. ¹HNMR (400 MHz, CDCl₃) δ 2.46 (s, 3H). MS (ESI): m/z 421 (M+H⁺, base).

A solution of the methylthioimidate (174 mg, 0.4 mmol) and acetichydrazide (31 mg, 0.4 mmol) in DCE (1 mL) was heated at 100 C for 16 hr.The dark brown mixture was evaporated and the residue waschromatographed (graded elution with 3:2 CH₂Cl₂:ether to 3:2CH₂Cl₂:ether with 2% methanol) to yield, upon trituration withdiisopropyl ether, 49 mg of Ic-14 as a tan powder. ¹H NMR (400 MHz,CDCl₃) δ 4.25 (m, 1H), 3.65 (s, 3H), 2.61 (s, 3H). MS (ESI): m/z 429(M+H⁺, base).

The following example was prepared according to the procedure set forthabove in Example Ic-14:

EXAMPLE Ic-15

¹H NMR (400 MHz, CDCl₃) δ 4.21 (m, 1H), 3.66 (s, 3H), 2.66 (s, 3H). MS(AP+): m/z 429 (M+Na⁺, base).

EXAMPLE Ic-16

Example Ic-16 was prepared using Otera's catalyst, sec-butyl alcohol,and methyl ester Ic-15 according to the procedure set forth in ExampleI-14.

96%; ¹H NMR (400 MHz, CDCl₃) δ4.22 (m, 1H), 3.83 (d, 2H), 2.66 (s, 3H),1.88 (m, 1H), 0.88 (d, 6H).

EXAMPLE Ic-17

In a round-bottomed flask was dissolved Int-17 (0.84 g, 1.69 mmol) inmethylene chloride (10 mL). To this was added trifluoroacetic acid (8.00mL) and the resulting solution was stirred overnight at roomtemperature. The reaction was concentrated to dryness and the residuewas taken up in a 0.5 M sodium carbonate solution. The aqueous layer waswashed twice with chloroform and once with diethyl ether (filtrationthrough Celite was used to break up any emulsions). The aqueous layerwas then adjusted to a pH of 4.5 using 1M phosphoric acid. The waterlayer was then extracted with ethyl acetate and chloroform. The combinedorganic extracts were dried over magnesium sulfate, filtered andconcentrated to give the carboxylic acid (0.47 g, 1.06 mmol) which wasdissolved in 1,2,4-trichlorobenzene and heated to reflux (214° C.) for30 min. The reaction was cooled to room temperature and loaded onto asilica gel pad. The pad was eluted with chloroform then the product waseluted with 3% methanol in chloroform to provide Ic-17 (0.35 g, 0.88mmol). ¹H NMR (CDCl₃): 8.05 (br s, 1H), 7.52-7.6 (m, 3H), 7.4-7.46 (m,1H), 7.27 (d, 1H, J=1.6 Hz), 7.22 (t, 1H, J=7.8 Hz), 7.0-7.19 (m, 2H),4.15 (dd, 1H, J=3.6, 5.2 Hz), 3.69 (s, 3H), 2.74-2.84 (m, 1H), 2.62-2.73(m, 2H), 2.50-2.60 (m, 1H). MS (ES+)=398(100%, M+).

EXAMPLE Ic-18

t-Butyl acrylate (45 mL) was added to a stirred solution of 3.25 g (10mmol) midazolam in 20 ml THF. The solution was cooled to −15° C., and 20ml 1.0M solution of potassium t-butoxyde in t-butanol was added over 10min. The mixture was stirred for 1 h at −10° C., then diluted with 500ml ether. The solution was washed with brine 3 times, dried withanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified using silica gel chromatography (hexane-ethylacetate (1:1)), providing 2.55 g of the ester. (56%) ¹H-NMR (CDCl₃) δ7.7-6.9 m (8H), 3.95 dd (J=4.7, 9.0, 1H), 2.7-2.4 m (4H), 2.51 s (3H),1.39 s (9H). MS: 454 (M+1, ES+).

TFA (100 mL) was added to a stirred solution of 2.42 g (5.3 mmol) tBuester in methylene chloride (100 mL). The mixture was stirred at 20° C.for 2 h, then concentrated under reduced pressure. The residue wasdissolved in chloroform (300 ml) then the solvent was evaporated. 50 mlDMF, 10 g potassium carbonate and 1.5 g methyl iodide was added to theresidue, then the reaction was stirred at 20° C. for 90 min. The mixturewas diluted with 300 ml ether, extracted with 200 ml water five times,and the organic phase was dried with anhydrous magnesium sulfate andconcentrated under reduced pressure. 10 ml ether was added to theresidue, and the solution was stirred at 0° C. for 30 min. The whitepowder was filtered and dried under vacuum to obtain 1.07 g ofrac-Ic-18. (49%) ¹H-NMR (CDCl₃): δ 7.60 m (2H), 7.40 m (2H), 7.22 m(2H), 7.00 t (J=10, 1H), 6.90 s (1H), 4.03 dd (J=4.8, 9.0, 1H), 3.68 s(3H), 2.8-2.4 m (4H), 2.54 s (3H). MS: 412 (M+1, ES+).

Separation of the enantiomers of rac-Ic-18 can be performed bypreparative chiral chromatography (Daicel AD column 5×50 cm, 20 micron;20% IPA/Hexane, 50-80 ml/min, UV 270 nM). The two enantiomers have thefollowing optical properties: (+)-Ic-18 t_(ret): 13.5 min.,[α]_(D)=+13.3 (THF, c=25 mg/ml); (−)-Ic-18: t_(ret): 21.8 min,[α]_(D)=−13.2 (THF, c=29 mg/ml).

EXAMPLE Ic-19

To the iminophosphate Int-19 (15 g) was added a 50 mL of 1M THF solutionof DL-serinol, t-butyl ether (prepared according to Meyers et al. J.Org. Chem. 1993, 58, 3568). Stirred at rt for 16 h, added an additional2 equiv. of amino alcohol. Heated to reflux for 1.5 h then standardaqueous extractive workup (DCM). Flash chromatography (3:1,hexanes:acetone) provided 7.7 g (62%) of the intermediate amidine. Theamidine was converted to example Ic-19 using general procedure I,followed by a TsOH/DMF cyclodehydration step as described in exampleIc-5. ¹H NMR (400 MHz, CDCl₃) δ 4.50 (dd, 2H), 4.03 (m, 1H), 3.66 (s,3H), 1.29 (s, 9H). MS (ES): 484 (M+1⁺).

When used in medicine, the salts of a compound of the invention shouldbe pharmaceutically acceptable, but pharmaceutically unacceptable saltsmay conveniently be used to prepare the corresponding free base orpharmaceutically acceptable salts thereof. Such pharmaceuticallyacceptable salts include, but are not limited to, those prepared fromthe following acids: hydrochloric, hydrobromic, sulfuric, nitric,phosphoric, salicylic, p-toluenesulfonic, tartaric, citric,methanesulfonic, maleic, formic, malonic, succinic, isethionic,lactobionic, naphtalene-2-sulfonic, sulfamic, ethanesulfonic andbenzenesulfonic.

Moreover, while it is possible for the compounds of the invention to beadministered as the bulk active chemicals, it is preferably presentedwith an acceptable carrier in the form a pharmaceutical formulation. Thecarrier must, of course, be acceptable in the sense of being compatiblewith the other ingredients of the formulation and must not bedeleterious to the recipient. Accordingly, the present inventionprovides a pharmaceutical formulation which comprises a compound ofFormula (I) as hereinbefore defined and a pharmaceutically acceptablecarrier in the form a pharmaceutical formulation. The formulationsinclude those suitable for oral, rectal, topical, buccal (e.g.sub-lingual) and parenteral (e.g., subcutaneous, intramuscular,intradermal or intravenous) administration. It is preferred to presentcompounds of the present invention in the form of a pharmaceuticalformulation for parenteral administration, e.g., by intravenous orintramuscular injection of a solution. Where the pharmaceuticalformulation is for parenteral administration, the formulation may be anaqueous or non-aqueous solution or mixture of liquids, which may containbacteriostatic agents, antioxidants, buffers or other pharmaceuticallyacceptable additives. The preferred formulations of compounds of Formula(I) of the present invention is by either an aqueous acidic medium of pH2-4 or by use of an aqueous solution of a cyclodextrin. Cyclodextrinsthat can be used for these formulations are either the anionicallycharged sulfobutylether (SBE) derivatives of β-CD, specificallySBE7-β-CD, marketed under the tradename Captisol by CyDex, Inc.(Critical Reviews in Therapeutic Drug Carrier Systems, 14 (1), 1-104(1997)), or the hydroxypropyl CD's. The preferred method of formulation(i.e., acid buffer or CD-based) may depend on the physicochemicalproperties (e.g., aqueous solubility, pKa, etc.) of a particularcompound. Alternatively the compounds may be presented as lyophilizedsolids for reconstitution with water (for injection) or dextrose orsaline solutions. Such formulations are normally presented in unitdosage forms such as ampoules or disposable injection devices. They mayalso be presented in multi-dose forms such as a bottle from which theappropriate dose may be withdrawn. All such formulations should besterile.

Accordingly, the present invention also provides a method for producingsedation or hypnosis in a mammal, which comprises administering to themammal an effective sedative or hypnotic amount of a compound of thepresent invention as hereinbefore defined. The present invention alsoprovides a method for inducing anxiolysis in a mammal, which comprisesadministering to the mammal an effective anxiolytic amount of a compoundof the present invention as hereinbefore defined. The present inventionalso provides a method for inducing muscle relaxation in a mammal, whichcomprises administering to the mammal an effective muscle relaxantamount of a compound of the present invention as hereinbefore defined.The present invention also provides a method for treating convulsions ina mammal, which comprises administering to the mammal an effectiveanticonvulsant amount of a compound of the present invention ashereinbefore defined.

The present invention also provides the use of a sedative or hypnoticamount of a compound of the present invention as hereinbefore defined inthe manufacture of a medicament for producing sedation or hypnosis in amammal, including in a human. The present invention also provides theuse of a anxiolytic amount of a compound of the present invention ashereinbefore defined in the manufacture of a medicament for producinganxiolysis in a mammal, including in a human. The present invention alsoprovides the use of a muscle relaxant amount of a compound of thepresent invention as hereinbefore defined in the manufacture of amedicament for producing muscle relaxation in a mammal, including in ahuman. The present invention also provides the use of an anticonvulsantamount of a compound of the present invention as hereinbefore defined inthe manufacture of a medicament for treating convulsions in a mammal,including in a human.

Intravenous administration can take the form of bolus injection or, moreappropriately, continuous infusion. The dosage for each subject mayvary, however, a suitable intravenous amount or dosage of the compoundsof the present invention to obtain sedation or hypnosis in mammals wouldbe 0.01 to 5.0 mg/kg of body weight, and more particularly, 0.02 to 0.5mg/kg of body weight, the above being based on the weight of thecompound which is the active ingredient. A suitable intravenous amountor dosage of the compounds of the present invention to obtain anxiolysisin mammals would be 0.01 to 5.0 mg/kg of body weight, and moreparticularly, 0.02 to 0.5 mg/kg of body weight, the above being based onthe weight of the compound which is the active ingredient. A suitableintravenous amount or dosage of the compounds of the present inventionto obtain muscle relaxation in mammals would be 0.01 to 5.0 mg/kg ofbody weight, and more particularly, 0.02 to 0.5 mg/kg of body weight,the above being based on the weight of the compound which is the activeingredient. A suitable intravenous amount or dosage of the compounds ofthe present invention to treat convulsions in mammals would be 0.01 to5.0 mg/kg of body weight, and more particularly, 0.02 to 0.5 mg/kg ofbody weight, the above being based on the weight of the compound whichis the active ingredient.

Thus a suitable pharmaceutical parenteral preparation for administrationto humans will preferably contain 0.1 to 20 mg/ml of a compound of thepresent invention in solution or multiples thereof for multi-dose vials.

The compounds of the present invention elicit important and measurablepharmacological responses. The compounds described by this inventionbind with high affinity to the benzodiazepine site on the GABA_(A)receptor complex (“benzodiazepine receptor”). The binding affinity wasmeasured by use of the following benzodiazepine radioligand bindingassay.

Tissues: Membrane homogenates were prepared from male Sprague Dawley ratbrain (whole brain less cerebellum), female Yucatan micropig braincortex and female human brain cortex according to the methods describedby Marangos & Martinos (Molecular Pharmacology 20:16-21, 1981). Thehuman donor was a 72 year old female Caucasian who died of an acutecardiopulmonary aneurysm. All tissues were obtained from, and membranehomogenates were prepared by Analytical Biological Services (ABI,Wilmington, Del.). Homogenates were frozen, stored at minus 80° C. andthawed immediately before use in radioligand binding assays.

Materials: ³H-flunitrazepam (NET-567) was obtained from New EnglandNuclear, Boston, Mass. 2′-chlorodiazepam was prepared at Glaxo Wellcome,RTP, USA. Tris HCl was obtained from GibcoBRL and sodium chloride wasobtained from J. T. Baker. Microscint-20 liquid scintillant andUnifilter 96 well plates were purchased from Packard Instruments.Midazolam and chlordiazepoxide were purchased from Sigma Chemicals.Flumazenil was a gift from Hoffman LaRoche.

Assay conditions: Test compounds were prepared in 100% DMSO at aconcentration of 25-50 mM. Compounds were diluted in assay buffer suchthat the first well contained 100 μM (final concentration). Eleven3-fold serial dilutions were prepared in buffer to complete a 12-pointconcentration-response curve for each test compound. Each concentrationwas tested in triplicate and compounds of interest were tested on atleast 3 separate occasions. The final concentration of DMSO in each welldid not exceed 0.4%. Nonspecific binding was defined in the presence of10 μM 2′-chlorodiazepam (Ki=0.5 nM). The final concentrations of³H-flunitrazepam were 2 nM, 2 nM and 2.5 nM for rat, micropig and humanassays, respectively. The concentrations differed slightly among thetissues so that the signal-to-noise ratio was optimized and the lowestpossible concentration was used. Concentration-response curves formidazolam, chlordiazepoxide or flumazenil were conducted as controlswith each assay run. Radioligand, compounds and membrane homogenateswere incubated for 90 minutes at 4° C. in buffer consisting of 50 mMTris HCl, pH 7.4, containing 150 mM NaCl. All assays were conducted in96 well plates in a total assay volume of 200 mL. Protein concentrationswere 12, 9 and 15 micrograms/well for rat, pig and human preparations,respectively. The reaction was terminated by rapid filtration (PackardFiltermate-196) through 96-well GF/B filter plates (Packard # 6005177).The filters were washed 8 times with 200 μL/well with ice-cold Tris 50mM, pH7.4 (˜1.6 ml total). After drying, 20 μL of Microscint was addedto each well and the plates were sealed. Plates were counted using aPackard TopCount microtiter plate scintillation counter.

Data analysis: Data were analyzed, fitted to a single site equation, andIC₅₀ values were calculated using the Excel Addin Robosage (GlaxoWellcome Research Information Resources). Ki values were calculatedusing the equation of Cheng and Prusoff (Biochem. Pharmacol.22:3099-3108, 1973). Kd values of ³H-flunitrazepam used in Kicalculations were determined for each tissue in saturation bindingexperiments. TABLE 1 Benzodiazepine receptor binding (Ki measured in nM;1-50 nM = ++++; 51-100 nM = +++; 101-1000 nM = ++; >1,000 = +) ExampleNo. Ki (nM) 1-1 ++++ 1-2 +++ 1-3 ++++ 1-4 ++ 1-5 ++++ 1-6 ++ 1-7 ++++1-8 ++++ 1-9 ++ 1-10 +++ 1-11 ++ 1-12 ++ 1-13 ++++ 1-14 ++ 1-15 ++ 1-16++++ 1-17 ++ 1-18 ++ 1-19 ++ 1-20 ++++ 1-21 ++++ 1-22 ++ 1-23 ++++ 1-24+++ 1-25 +++ 1-26 +++ 1-27 ++++ 1-31 +++ 1b-1 +++ 1b-2 + 1b-3 ++ 1b-4 ++1b-5 + 1b-6 ++ 1b-7 + 1b-8 ++ 1b-9 ++ 1b-10 ++++ 1c-1 ++++ 1c-2 ++++1c-3 ++++ 1c-4 ++++ 1c-5 ++++ 1c-6 +++ 1c-7 +++ 1c-8 ++++ 1c-9 ++++1c-10 +++ 1c-11 ++ 1c-12 ++ 1c-13 ++ 1c-14 ++++ 1c-15 ++++ 1c-16 ++++1c-17 ++ 1c-18 ++++ 1c-19 ++++

High affinity binding of a ligand to the benzodiazepine receptor doesnot characterize the intrinsic efficacy (full agonist, inverse agonist,antagonist) of a benzodiazepine receptor ligand. The intrinsic efficacyof a compound was assessed by its ability to cause loss of the rightingreflex (LRR) in rats, an effect associated with benzodiazepine fullagonism.

Method: Subjects for these studies were male Wistar rats, weighingapproximately 250-350 grams. To assess loss of righting reflex (LRR),animals were placed in plastic restrainers and test compounds wereadministered i.v. via the tail vein. Subjects were immediately removedfrom the restrainer and the time to onset of loss of righting reflex wasrecorded. LRR was defined as the loss of an animal's ability to rightitself when placed in a supine position. A compound was identified asinactive in this model if LRR was not observed within 5 minutesfollowing injection. Compounds producing LRR were evaluated by threemeasures: 1) Time to onset of LRR (as described above) 2) Time torecover from LRR. An animal met this criteria when able to right itselfthree consecutive times after losing its righting reflex 3) Totalrecovery time. Total recovery was measured by the animal's ability towalk without ataxia as well as its ability to pull itself up threeconsecutive times when suspended from a horizontal wire. Compoundsproducing loss-of-righting at a dose in the range of 10-100 mg/kginclude the following: examples 1, 3, 4, 5, 6, 7, 9, 11, 17, 23 ofcompounds of Formula Ia, examples 1 and 10 of compounds of Formula Iband examples 1, 2, 3, 6, 7, 8, 10, 14, 15, 17, 18 of compounds ofFormula Ic. In the rat loss-of-righting model at a dose range of 10-100mg/kg, the compounds of this invention displayed overt pharmacologicalresponses similar to those of therapeutically useful benzodiazepinesdescribed in the prior art. The therapeutically useful dosage range foradministration to mammals is 0.01 to 5.0 mg/kg of body weight.

1-30. (canceled)
 31. A compound of formula (I):

wherein W is H, a C₁-C₄ branched alkyl, or straight chained alkyl; X isCH₂, NH or NCH₃; n is 1 or 2; Y is O or CH₂; m is 0 or 1, provided thatif X is CH₂, n is 1 and m is 0, then R¹ is not CH₂CH₃; R¹ is H, a C₁-C₇straight chain alkyl, a C₃-C₇ branched chain alkyl, a C₁₋₄haloalkyl, aC₃-C₇ cycloalkyl, an aryl, a heteroaryl, an aralkyl, or a heteroaralkyl;R² is phenyl, 2-halophenyl or 2-pyridyl, R³ is H, Cl, Br, F, I, CF₃ orNO₂; R⁸ is hydrogen, C₁₋₄alkyl or C₁₋₃hydroxyalkyl; U is CR⁹ where R⁹ isH, C₁₋₄alkyl, C₁₋₃hydroxyalkyl, C₁₋₄alkoxy, or C₁₋₄alkyl; and V is CH;or a pharmaceutically acceptable salt or solvate thereof.
 32. A compoundof claim 31 wherein W is H; X is CH₂, n is 1; Y is CH₂, m is 1; R¹ isCH₃ or CH₂CH(CH₃)₂; R² is 2-fluorophenyl, 2-chlorophenyl or 2-pyridyl;R³ is Cl or Br; and R⁸ is H, CH₃ or CH₂OH.
 33. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and aneffective amount of a compound of claim
 31. 34. A pharmaceuticalformulation comprising a pharmaceutically acceptable carrier and aneffective amount of a compound of claim
 32. 35. A method of producingsedation or hypnosis, inducing anxiolysis, inducing muscle relaxation ina mammal, or treating convulsions in a mammal, comprising: administeringto the mammal an effective amount of a compound of claim
 31. 36. Themethod of claim 35 wherein the mammal is in need of sedation.
 37. Themethod of claim 35 wherein the mammal is in need of hypnosis.
 38. Themethod of claim 35 wherein the mammal is in need of muscle relaxation.39. The method of claim 35 wherein the mammal suffers from convulsions.40. A method of producing sedation or hypnosis, inducing anxiolysis,inducing muscle relaxation in a mammal, or treating convulsions in amammal, comprising: administering to the mammal an effective amount of acompound of claim 32.